AU751386B2 - Crystal of SM3 antibody (fragment) and recognizing epitope, its preparation, encoded data storage medium containing its coordinates and its diagnostical or medical use - Google Patents

Description

WO 99/10379 PCT/GB98/02542 CRYSTAL OF SM3 ANTIBODY (FRAGMENT) AND RECOGNIZING EPITOPE, ITS PREPARATION, ENCODED DATA STORAGE MEDIUM CONTAINING ITS COORDINATES AND ITS DIAGNOSTICAL OR MEDICAL USE The present invention relates to a process for preparing a crystal, to the use of structural coordinates of a crystal comprising the epitope binding fragment of an antibody bound to a peptide, to mimics of the antibody and peptide, to products recognisable by mimics of the antibody or which recognise mimics of the peptide, to engineered antibodies and to their use in diagnosis or therapy.

Introduction The monoclonal antibody SM3 (secreted by the hybridoma HSM3 deposited with ECACC on 7 January 1987 under accession no. 87010701) binds to a tumour associated epitope on the epithelial mucin MUC1 (WO-A- 88/05054, WO 90/05142).

The MUC1 epithelial mucin is a transmembrane glycoprotein with the extracellular domain made up largely of exact tandem repeats of 20 amino acids, each of which contains five potential glycosylation sites (Gendler et al. 1988, 1990; see Figure In breast and other carcinomas MUC1 is over-expressed and is aberrantly glycosylated making it antigenically distinct from the normally processed mucin. In breast cancers, the 0glycans which are added are shorter (Hanish et al., 1989; Hull et al., 1989; Lloyd et al., 1996), resulting in the exposure of epitopes which are normally masked on the core protein (Burchell and Taylor-Papadimitriou, 1993).

Such epitopes are called cryptic epitopes. The SM3 antibody was raised against MUC1 stripped of its carbohydrate (Burchell et al., 1987). SM3 recognises such a cryptic epitope, and shows high selectivity in reacting specifically with the carcinoma associated mucin WO 99/10379 PCT/GB98/02542 -2in more than 90% of breast carcinomas (Girling et al., 1989). The high specificity of the SM3 antibody makes it a potentially useful tool in the diagnosis and treatment of breast cancer (Granowska et al., 1996).

The sequence of the repeating unit of the core protein of MUC1 contains doublets of threonine and serine, bounding a highly immunogenic domain (Burchell et al., 1989; see Figure A three-dimensional

NMR

structure for three multiple MUC1 peptide repeats reveals repeating "knob-like" structures, corresponding to the immunogenic domains which are connected by extended spacers (Fontenot et al., 1995). The epitope for SM3 has been mapped using overlapping peptides and found to correspond to just five contiguous amino acids, Pro-Asp- Thr-Arg-Pro (Burchell et al., 1989, hereafter referred to as the MUC1 epitope) lying within the "knob-like" domain and between the potential serine and threonine glycosylation sites. In vitro studies using recombinant GalNAc transferase which adds the first sugar to Ser or Thr suggest that Thr 1 Ser 12 and Thr 13 are glycosylated, while Thr 6 (within the MUC1 epitope) and Ser 2 are not (Wandall et al., 1997).

The inventors have crystallised a fragment of SM3 bound to a peptide, subjected the crystal to X-ray diffraction studies and measured the structure factors.

From the structure factors they have solved the structural coordinates. These may be used to generate new diagnostic and therapeutic materials and for other investigative purposes.

The invention includes the use of the structure factors and/or structural coordinates to identify, characterise, design or screen chemical entities, which have uses in diagnosis and therapy, as will be discussed below.

In one aspect the present invention provides the WO 99/10379 PCT/GB98/02542 -3use of the structure factors and/or structural coordinates obtainable by subjecting a crystal comprising at least the epitope binding fragment of the SM3 antibody, bound to a peptide recognised by the epitope binding site of SM3 to X-ray diffraction measurements and optionally thereafter analysing the diffraction measurements to deduce structural coordinates.

The invention particularly provides a use of the structural coordinates of a moiety which comprises at least the epitope binding fragment of the SM3 antibody or a substantially similar fragment bound to a peptide such as the crystal peptide. The moiety may be whole SM3 antibody, or a Fab fragment de-rived- from the d-igestion of whole SM3 antibody by papain. The moiety may comprise a modified form of whole SM3 or a modified form of a fragment of SM3. Such modifications include the insertion or deletion of amino acids, or replacement of amino acids by other amino acids. Other chemical modifications may be made.

The peptide may comprise the sequence Pro-Asp-Thr- Arg-Pro, or any longer portion of the MUC1 tandem repeat, for instance the sequence Thr-Ser-Ala-Pro-Asp-Thr-Arg- Pro-Ala-Pro-Gly-Ser-Thr.

The invention provides the use of the structure factors and/or structural coordinates of a crystal of the Fab fragment of SM3 bound to the crystal peptide. The structure factors of such a crystal obtained as in the Examples are shown in Table 1 and the structural coordinates are shown in Tables 2a and 2b. The structural coordinates shown in each of Tables 2a and 2b are derived from the structure factors. However the coordinates shown in Table 2b have been calculated to a higher refinement and include additional protein atoms.

The invention provides the use of the structural coordinates shown in Table 2a and/or Table 2b.

WO 99/10379 PCT/G B98/02542 -4- The structural coordinates indicate the positions of individual atoms within the crystal and indicate the B factor for each atom which gives some information about the mobility of the atoms. The structure factors may be used to derive additional information about the mobility of any individual atom or group of atoms within the crystal. This additional information, for instance, anisotropic B factors, may concern the direction of movement possible for each atom. The structure factors and structural coordinates thus give an indication of the available space for adjusting the position of individual atoms when designing mimics of the peptide or antibody.

Mimics of SM3 The invention provides the use of structure factors and/or structural coordinates to identify, characterise, design or screen mimics of SM3. The structural coordinates allow the epitope binding site bound to the peptide to be shown as a two dimensional representation, for example as in the LIGPLOTs of Figures 8 to 11 or a three dimensional representation by physical models or as displayed on a computer screen. Such representation can be used to design modifications of SM3. Such modifications includes modifications to increase the avidity of the epitope binding site for the bound peptide. This modification may preferentially increase the avidity of the epitope binding site for abnormally glycosylated MUC1.

The avidity may be increased by modifying the epitope binding site structure to increase the amount and number of interactions favourable to peptide binding and/or diminish unfavourable interactions between the peptide and antibody. Favourable interactions may be increased by extending the structure of the epitope binding site into spaces which are shown in the two WO 99/10379 PCT/GB98/02542 dimensional or three dimensional representations to be unoccupied or filled with water molecules. Such water molecules may include those which are shown in Figures 8 to 11.

The representations of the structures may be used in other ways to modify the structure of SM3. It is believed that SM3 may bind the peptide by an "induced fit" method which requires that conformation changes occur in the structure of SM3 during the process of binding the peptide. The SM3 binding site, or other parts of SM3 may be modified to allow such changes to occur more easily. Alternatively the mimic of SM3 may comprise the SM3 epitope binding site constrained in the conformation it adopts when it binds the peptide. The representations of the epitope binding site may be used to model such constraints by the putative introduction of covalent bonds between the atoms of SM3 which come close together when SM3 binds the peptide; one or more chemical linkers may be used between atoms of SM3 to constrain the epitope binding site to the required conformation, and/or one or more amino acids of SM3 may be replaced by analogues of the natural amino acids which help to constrain the conformation of the epitope binding site.

On the basis of such modelling SM3 mimics may be identified, characterised, designed or screened.

It is believed that the reason why SM3 has a low avidity for aberrantly glycosylated MUCI is steric hindrance between residues close to or in the epitope binding site and carbohydrate moieties attached to positions 1, 12 and 13 of the peptide as shown in Figure i. The representation of the epitope binding site bound to the peptide may be used to predict which residues of SM3 are likely to be involved in the steric hindrance.

One such residue may be Proline 56 of SM3. Such residues may be modified, replaced or deleted to decrease the WO 99/10379 PCT/GB98/02542 -6steric hindrance in order to increase avidity.

Mimics of SM3 may for instance be obtained by computer modelling techniques. Using the structural coordinates a three dimensional representation of the surface of the epitope binding site bound to the peptide can be produced using Catalyst Software such as Catalyst/SHAPE, Catalyst/COMPARE, DBServer HipHop Ludi, MCSS and Hook which are available from Molecular Simulations Ltd., 240/250 The Quorum, Barnwell Road, Cambridge, England. Mimics of SM3 can be produced eitherby computationally identifying compounds which have a similar surface to the binding site of SM3, or by computationally designing compounds with surfaces which are likely to bind the peptide. Various methods can then be used to produce a three dimensional surface which is the same or similar to the epitope binding surface.

Based on this shape, packages such as Catalyst/SHAPE and Catalyst/COMPARE can be used to select compounds from databases which have a similar three dimensional shape to the epitope binding site. The epitope binding site surface may be described in more detail by analysis of the functional groups present to produce a pharmacophore.

Based on a pharmacophore, packages such as DBServerl and HipHop can be used to search databases for compounds whose surfaces are described by similar pharmacophores.

The databases that can be searched include ACD, NCI, Maybridge, Derwent World Index and BioByte.

Packages such as Ludi and MCSS can be used to select fragments or chemical entities from databases which can then be positioned in a variety of orientations, or "docked" with the surface of the peptide. Once suitable chemical entities or fragments which bind sites on the surface of the peptide have been identified bridging fragments and framework structure are chosen with the correct size and geometry to support the WO 99/10379 PCT/GB98/02542 -7chemical entities and fragments in the favourable orientation and location and to form the mimic of SM3.

Packages such as Hook can be used to select framework structures.

Once a candidate mimic of SM3 has been designed or selected by the above methods, the efficiency with which that mimic may bind to the peptide may be tested and optimized using computational or experimental evaluation.

Various parameters can be optimized depending on the desired result. These include, but are not limited to, specificity, avidity, on/off rates, and other characteristics readily identifiable by the skilled artisan.

The computational means may employ packages such as Catalyst/SHAPE, Catalyst/COMPARE, DBServer, HipHop, Ludi and MCSS to evaluate selected candidate SM3 mimics. The experimental means may comprise ELISA methods such as detailed below using GST-MUCl ELISA plates or the techniques described in Bynum et al.

Thus, one may optionally make substitutions, deletions, or insertions in some of the components of the SM3 mimics in order to improve or modify the binding properties. Generally, initial substitutions are conservative, i.e. the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original component. Such modified mimics can be computationally or experimentally evaluated in the same manner as the first candidate SM3 mimics, and if necessary further modifications can be made. This process of evaluating and modifying may be iterated any number of times.

The term aberrantly glycosylated MUC1 is used throughout this specification to refer to MUCI which has a different level of glycosylation than is normally found on MUCI from a particular tissue. The different level of WO 99/10379 PCT/GB98/02542 -8glycosylation may be a decrease in the level of glycosylation. MUC1 with such decreased levels of glycosylation may be produced by a tumour cell, such as an adenocarcinoma cell for instance a cell from an epithelial tumour of colon, lung, ovary, pancreas or especially a breast tumour cell.

Mimics of SM3 preferably have a high avidity for aberrantly glycosylated MUC1. Such an avidity may be higher than that of SM3. They may have a higher selectivity towards aberrantly glycosylated MUC1 in preference to normally glycosylated MUC1 than SM3.

The avidity of the mimic of SM3 to bind aberrantly glycosylated MUC1 can be tested in an ELISA assay as detailed below: GST-Muc-1 ELISA Method Preparation of GST-Muc-1 Batch 5 ELISA plate.

DNA coding for the seven tandem repeats of the 20 amino acid peptide epitope was cloned into a GST fusion vector, pGEX-2T (Pharmacia) in the E.Coli strain TG1 The cells were grown in L broth (100mg/ml ampicillin) overnight and then IPTG was added to a final concentration of 0.5 mM followed by a further incubation of 4 hr at 37 C The cells were pelleted (20min/10000rpm), washed x2 with PBSa and resuspended in 25mM TRIS pH 8, 25mM Glucose, 10 mM EDTA containing lyzozyme (4mg/ml) and left for 30 min at RT. 5ml of lysis buffer was then added and incubated on ice for 5 min. After centrifugation the supernatant was loaded onto a Glutathione Sepharose 4B column (Pharmacia) equilibrated in lysis buffer. The fusion protein product was eluted in PBSa/15mM Glutathione and stored at 4 C until required. SDS-PAGE and FPLC Superose 6 (Pharmacia) size separation showed a single species mwt 43 K.

Preparation of GST-Muc-1 Batch 5 ELISA Plates The GST-Muc-1 was diluted in PBSa to 50mg/ml and WO 99/10379 PCT/GB98/02542 -9added to each well of a 96 well plate The plates were incubated overnight at 4 C, blocked with 200ml 2% BSA/PBSa for 2 hr at RT. and stored at -70 C until required.

REAGENTS/BUFFERS

Alkaline Phosphatase -Goat anti-mouse (Fc Specific) Sigma No. A-2429 BSA Albumin Bovine, Fraction V powder, RIA grade, Sigma No A-7888 ELISA Plates Nunc-Immuno Plates No. 442404 ELISA Substrate Buffer Diethanolamine buffer pH 9-8 400ml Diethanolamine (Sigma D-2286) 24.5 mg MgC12 BHD (Anala R) pH 9.8 with HC1 and make up to 500ml with distilled water EDTA Ethylenediamine tetra acetic acid BDH Anala R Glutathione Reduced ICN 101814 IPTG Isopropylthio-b-D-galactoside Promega Lysis Buffer 150mM NaCI, 16 mM Na2HP04, 4mM NaH2PO4, 100mM EDTA, 1% Triton X (BDH Anala R) 2 mM PMSF (Phenylmethylsulfonyl fluoride) (Sigma) pNPP p-Nitrophenyl Phosphate Sigma No. N-9389 PBSAa- Phosphate Buffered Saline (ICRF) TWEEN 20 Polyoxyethylene (20) Sorbitan monolaurate WO 99/10379 PCT/GB98/02542 BDH 66368 GST-Muc-1 (a Glutathione-S-transferase fusion protein containing seven copies of the 20 amino acid tandem repeat (non-glycosylated) ELISA plates are stored -70 0 C pre blocked with 2% BSA/PBSA. (PBSA- Phosphate Buffered Saline BSA- Bovine Serum Albumin, Fraction V powder, RIA grade, Sigma No. A-7888.) 1. Thaw out a plate at room temperature (RT).

2. Test antibody samples are diluted in PBSA/ 0.02% Tween 20 (PBSA/T). e.g. SM3 from 100-0.001 mg/ml.

3. Wash the plate three times with PBSA/T. Add samples in a volume of 50 ml, in triplicate and leave at RT for 1 hour.

4. Remove the antibody samples carefully by aspiration and add 200 ml of PBSA/T to each well. Remove by aspiration and repeat. Then wash again twice with

PBSA/T.

5. Add 50 ml of 1/2000 (diluted PBSA/T) Goat anti-mouse (Fc Specific) Alkaline Phosphatase (Sigma No.

A-24209) to each well and incubate at RT. for 1 hour.

6. Wash the plate three times with PBSA/T and then add 50ml of substrate which is p-Dinitrophenyl Phosphate (Sigma N-2765) at Img/ml in Diethanolamine Buffer pH 9.8, (400ml distilled water, 48ml diethanolamine, 24.5mg MgCl 2 pH 9.8 with HC1 and make up to 500ml with distilled water).

7. Incubate at RT. for 15 min and read the OD at 405 nm on the Labsystems Multiscan Plate reader.

The avidity of the mimic of SM3 can also be measured using methods described in Bynum et al.

These techniques may also be used to test the specificity of the mimic of SM3 by testing the avidity of the mimic for aberrantly glycosylated MUC1 and for WO 99/10379 PCT/GB98/02542 -11normally glycosylation MUC1.

A histological screen using the mimic of SM3 can be performed using tumour tissue from a breast tumour and normal tissue, for example, as described in Girling et al., 1989. This can be used to determine if the mimic is specific for the aberrantly glycosylated MUC1 and therefore suitable for use in a method of diagnosing breast cancer. The mimic can also be tested against live tumour cells which are not fixed.

Cells which have MUC1 with reduced levels of glycosylation can be produced by the use of metabolic inhibitors of O-linked chain extension, such as Obenzylgalactosamine. Such cells can be used to study the effects of low levels of glycosylation of MUC1 on the avidity of the mimics of SM3.

Mimics of SM3 may be used in a diagnostic test to detect the presence of tumour cells in a tissue sample, for example in a histological screening. Mimics used in this manner may be labelled with a detectable label.

Alternatively agents able to specifically bind such mimics may be used to detect the presence of the mimics once the mimics have bound the aberrantly glycosylated.

The mimics of SM3 may be used in vivo for the detection of tumour cells. They may be used in tumour imaging in vivo. Generally, such mimics would be labelled with a detectable label.

The mimics of SM3 can be used in a method of therapy against cancer, particularly adenocarcinomas such as ovary, colon, lung, pancreas and breast epithelial cancers, especially breast cancers.

Mimics which are antibodies or substantially similar to antibodies or fragments of antibodies may bind to aberrantly glycosylated MUC1 on the surface of tumour cells and aid the killing of the tumour cells by recruiting the patients immune system.

WO 99/10379 PCT/GB98/02542 -12- Mimics of SM3 may be chemically linked to a cytotoxic agents such as a toxin or a radioisotope.

Binding of such toxin linked mimics to the tumour cells would lead to the killing of the tumour cell.

It is believed that high levels of MUC1 or aberrantly glycosylated forms of MUC1 may have an immunosuppressive effect. Tumour cells may have high levels of MUC1 on their surface and/or aberrantly glycosylated forms. Therefore in the method of therapy of the invention a mimic of SM3 could be used to bind to MUC1 in vivo and prevent or decrease its immunosuppressive effects. The types of immunosuppressive effects that may be prevented or decreased are discussed below in relation to mimics of the MUC1 epitope. Such a mimic could be administered in conjunction with an antitumour agent, such as an anti-tumour vaccine, and may have an adjuvant-like effect (the mimic may increase the immune response generated by the vaccine). The antitumour agent could be a mimic of the SM3 epitope. The mimic of SM3 could be administered at any time in relation to the administration of the anti-tumour agent, for example before, with or after the administration of the anti-tumour agent.

Thus the invention provides a mimic of SM3 for use in a method for treatment of the human or animal body by surgery or therapy or in a diagnostic method practised on the human or animal body, such as in anti-cancer therapy.

The invention also provides a product comprising a mimic of SM3 and an anti-tumour agent as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

The invention provides a use of a mimic of SM3 in the production of a pharmaceutical composition for use in the methods discussed above. The invention provides a pharmaceutical composition containing a mimic of SM3 and WO 99/10379 PCT/GB98/02542 -13a diluent or carrier. The invention provides a method of treating or diagnosing cancer by administering to a human or non-human animal in need thereof an effective nontoxic amount of a mimic of SM3.

The production of mimics of SM3 and the methods, routes and dosages for use of the mimics of SM3 are discussed below.

Mimics of MUC1 epitope peptides The invention allows the use of the structure factors and the structural coordinates to identify, characterise or design a mimic of the MUCI epitope peptides. Such a mimic may be used to produce a specific binding agent which has a desired association with aberrantly glycosylated MUC1. The mimic of the peptide can be used to select a specific binding agent from a library on the basis of its affinity to the mimic. Such a library may be a microbial display library, such as a phage display library. The specific binding agent may bind aberrantly glycosylated MUC1, and therefore be used in a similar manner to the mimics of SM3. The mimic of the peptide may be used in a vaccine administered to a human or animal. Such a vaccine would stimulate the production of antibodies able to bind aberrantly glycosylated MUC1. Such a vaccine could therefore be used as a therapy against cancer, for example to prevent or treat cancer.

Thus the invention provides a mimic of the MUC1 epitope, a mimic of the MUCI epitope for use a method for treatment of the human or animal body by surgery or therapy or in a diagnostic method practised on the human or animal body, such as in anti-cancer therapy. The invention also provides a use of such a mimic in the production of a pharmaceutical composition for use in such a method. The invention provides a pharmaceutical composition containing a mimic of the MUC1 epitope and a WO 99/10379 PCT/GB98/02542 -14diluent or carrier therefor. The invention provides a method of diagnosing or treating cancer by administrating an effective non-toxic amount of a mimic of the MUC1 epitope to a human or non-human animal in need thereof.

The production of mimics of the MUC1 epitope and methods, routes and dosages for use of the mimics of the MUC1 epitope are discussed below.

The MUC1 epitope mimics may also be administered to an animal preferably a laboratory mammal, such as a rodent, for instance a mouse, in order to induce an antibody response. Antibody secreting cells may be recovered from the animal and hybridoma technology may then be used to produce a hybridoma using such recovered cells. The hybridoma or any other antibody expression system would be a source of monoclonal antibodies capable of recognising the mimic and preferably the MUC1 epitope and thus have diagnostic and therapeutic utilities as for the SM3 mimics described above.

As described above it is believed that MUC1 may cause immunosuppressive effects. Thus the mimic of the epitope may be capable of causing an immunosuppressive effect, and thus may be used to cause such an effect in a human or animal. The immunosuppressive effect may be caused by the mimic decreasing the activity of T cells, such as CD4 or CD8 T cells. The T cells may be polyclonal.

The mimic may cause a decrease in (i)the proliferation of the T cells, (ii) their secretion of cytokines, (iii) their interaction with other cells, such as interaction mediated by ICAM-1 on the T cell surface, and/or(iv)their cytotoxic activity. The mimic may cause the cross-linking of a surface molecule on the T cells, such as ICAM-1. The mimic may cause T cells to become anergic. The effects of the mimic may be reversible by the addition of IL-2 or anti-CD28 antibody.

WO 99/10379 PCT/GB98/02542 Thus the mimic may be used to decrease or prevent an immune response, particularly when the response has a deleterious effect on the body. Thus the mimic may be used in the therapy to treat or prevent) of diseases caused by autoimmune responses (such as arthritis, multiple sclerosis, asthma or diabetes), allergies, inflammatory disorders or transplant rejections, such as graft versus host disease.

Thus the invention provides a mimic of the MUC1 epitope for use in therapy which prevents or decreases an immune response, and so can treat or prevent a disease caused by an immune response. The invention also provides a use of such a mimic in the production of a pharmaceutical composition for use in such a method. The invention provides a method of treating a disease caused by an immune response, such as autoimmune disease, allergy, inflammatory disorder or transplant rejection; by administrating an effective non-toxic amount of a mimic of the MUC1 epitope to a human or non-human animal in need thereof.

As with the mimics of SM3 the two dimensional and three dimensional representations of the epitope binding site bound to the peptide mentioned previously can be used to design a mimic which is, for instance, a peptide or a derivative thereof or an analogue of a peptide comprising the sequence Pro-Asp-Thr-Arg-Pro or the sequence Thr-Ser-Ala-Pro-Asp-Thr-Arg-Pro-Ala-Pro-Gly-Ser constrained in the conformation approximately that which the crystal peptide adopts when bound to SM3.

The sequence can be constrained by the introduction of covalent bonds between atoms which come close together in the conformation adopted when bound to SM3.

Alternatively a chemical linker may be used to join such atoms together. The sequences may be constrained by cyclisation of a peptide in which the relevant sequence WO 99/10379 PCT/GB98/02542 -16is present. The peptides may also be constrained by replacement of one or more amino acids by analogues of natural amino acids which cause the peptide analogue to adopt the required conformation when they are introduced.

Hydrogen bonds, such as intra-peptide hydrogen bonds may be introduced into the mimic. These may help to constrain the mimic to a particular conformation, such as the conformation adopted when bound to SM3.

The structural coordinates allow the epitope binding site bound to the crystal peptide to be shown as a two dimensional representation, for example the LIGPLOTs of Figures 8 to 11 or a three dimensional representation on a computer screen. Such representation can be used to design modifications to the MUC1 epitope which may increase its avidity for SM3, for example, by increasing the "on rate" relative to the crystal peptide and decreasing the "off rate". The avidity of the MUC1 epitope mimic for the epitope binding site may be increased using a similar strategy as used to design mimics of SM3. The mimic can be modified to increase the amount and number of favourable interactions with SM3, for example by extending the structure of the MUC1 epitope into spaces which are shown to be unoccupied or filled with water molecules. Such water molecules may include those shown in Figures 8 to 11. It is appreciated that such mimics of the MUC1 epitope which are designed to have an increased avidity with the epitope binding site of SM3 may not cause the production of antibodies with a higher avidity to aberrantly glycosylated MUC1 than SM3 has, however such mimics may lead to the stimulation of an increased antibody response due to their higher avidity to the antibody. The two dimensional and three dimensional representation of the epitope binding site bound to the crystal peptide can as mentioned previously be used to determine why SM3 binds WO 99/10379 PCT/GB98/02542 -17the peptide with a low avidity. This information can then be used to design mimics of the MUC1 epitope which can select from a library those mimics of SM3 which have a high avidity to aberrantly glycosylated MUC1. Such mimics, when administered in a vaccine may also stimulate the production of antibodies with a higher avidity to aberrantly glycosylated MUC1 than SM3.

Such mimics of the MUC1 epitope may for example be designed by modifying the structure of the crystal peptide which binds SM3 in those areas where unfavourable interactions occur between the crystal peptide and epitope binding site which cause a lowering of avidity.

For example the structure of the MUC1 epitope may be extended in those areas where- steric hinderance occurs between the carbohydrates on the aberrantly glycosylated MUC1 and the epitope binding site. Use of such a mimic may lead to the selection of specific binding agents (as described above) from a library or the stimulation of antibodies which have a reduced level of steric hinderance with the carbohydrate and therefore a higher avidity for aberrantly glycosylated MUC1.

Mimics of the MUC1 epitope may be designed by computer modelling techniques in a similar manner to the designing of mimics of SM3 using these techniques.

Again, packages such as Catalyst/SHAPE and Catalyst/COMPARE can be used to select compounds with a similar three dimensional shape to the peptide when it is bound to SM3. Packages such as DBServer and HipHop can be used to find compounds with similar pharmacophores to the peptide and packages such as Ludi, MCSS and Hook can be used to design a mimic which is predicted to bind well to the epitope binding site of SM3.

Once a candidate mimic has been designed or selected by the above methods, the efficiency with which that mimic may bind to the SM3 epitope binding site may WO 99/10379 PCT/GB98/02542 -18be tested and optimized using computational or experimental evaluation. As described previously packages such as Catalyst/SHAPE, Catalyst/COMPARE, DBServer, Ludi and MCSS may be used to computationally evaluate the mimic. The mimic may be experimentally evaluated in the competition ELISA assay described below.

Various parameters can be optimized depending on the desired result. These include, but are not limited to, specificity, avidity, on/off rates, and other characteristics readily identifiable by the skilled artisan.

Thus, one may optionally make substitutions, deletions, or insertions in some of the components of the MUC1 epitope in order to improve or modify the binding properties. Generally, initial substitutions are conservative, i.e. the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original component.

As with the mimic of SM3 the process of evaluation and modification can be iterated any number of times.

The mimic of the MUC1 epitope may be glycosylated.

The mimic may have an intra-peptide hydrogen bond.

This may be between the residues equivalent to Pro 4 and Thr 6 of the MUC1 epitope or between the residues equivalent to Asp 5 and Arg 7. The atoms involved in the hydrogen bond may be the equivalent of Pro 4 (atom 0), Thr 6 (atom Asp 5 (atom OD1) and/or Arg 7 (atom N) The mimic of the MUC1 epitope may have higher avidity to SM3 than aberrantly glycosylated MUC1, or a low avidity or may not bind at all. The avidity of the mimic can be tested in a competition ELISA assay in which a MUC1 peptide such as aberrantly glycosylated MUC1, deglycosylated MUC1 or the fully stripped core protein or a fragment thereof is attached to the plate and SM3 is added in the presence of the mimic of the MUC1 epitope.

WO 99/10379 PCT/GB98/02542 -19- By measuring the ability of the mimic to inhibit the binding of the antibody to the MUC1 peptide the avidity of the mimic for SM3 can be measured. Preferred mimics include those which lead to the selection of specific binding agents from a library which bind aberrantly glycosylated MUC1 with a higher avidity and/or higher selectivity than SM3. Preferred mimics of the MUCI epitope are also those which stimulate the production of antibodies in vivo which have a higher affinity than SM3.

As discussed above specific binding agents include those which have been selected from a library, which may include antibodies, or those antibodies produced by B cells which bind the mimic of the peptide. Preferred specific binding agents are those which bind aberrantly glycosylated MUCI with an avidity and/or specificity higher than SM3.

The specific binding agents may be used in a diagnostic test to detect the presence of tumour cells in a tissue sample, for example in a histological screening.

Specific binding agents used in this manner may be labelled with a detectable label. Alternatively moieties able to specifically bind such mimics may be used to detect the presence of the specific binding agents once the specific binding agents have bound the aberrantly glycosylated.

The specific binding agents may be used in vivo for the detection of tumour cells. They may be used in tumour imaging in vivo. Generally, such specific binding agents would be labelled with a detectable label.

The specific binding agents may be used to prevent or decrease immunosuppression caused by MUC1.

The specific binding agents can be used in a method of therapy against cancer, particularly breast cancer.

Specific binding agents which are antibodies or substantially similar to antibodies or fragments of WO 99/10379 PCT/GB98/02542 antibodies may bind to aberrantly glycosylated MUCI on the surface of tumour cells and aid the killing of the tumour cells by the immune system.

Specific binding agents may be chemically linked to a cytotoxic agents such as a toxin or a radioisotope.

Binding of such toxin linked specific binding agents to the tumour cells would lead the killing of the tumour cell.

Thus the invention provides a specific binding agent for use a method for treatment of the human or animal body by surgery or therapy or in a diagnostic method practised on the human or animal body, such as in anti-cancer therapy. The invention also provides a use of a specific binding agent in the production of a pharmaceutical composition for use in such a method. The invention provides a pharmaceutical composition containing a specific binding agent and a diluent or carrier therefor. The invention also provides a method of diagnosing or treating cancer by administering an effective non-toxic amount of a specific binding agent to a human or non-human animal in need thereof.

The invention also provides a product comprising a specific binding agent and an anti-tumour agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.

The production of such specific binding agents and of the MUC1 epitope mimics and methods, routes and dosages for use of the agents and mimics are discussed below.

When administered to an animal or human the mimic of SM3 may lead to the production of antibodies which recognise the mimic. B cells from the animal or human may be used in conjunction with hybridoma technology to produce such antibodies as monoclonal antibodies. Such antibodies may have a epitope binding site which is WO 99/10379 PCT/GB98/02542 -21similar in shape to the crystal peptide. The administration of such antibodies to an animal or human may lead to the production of antibodies which recognise aberrantly glycosylated MUCI. Therefore the antibodies which recognise SM3 may be used as a vaccine or may be used to produce a vaccine against cancer.

The antibodies or fragments thereof which recognise aberrantly glycosylated MUCI produced in response to the anti-mimic of SM3 antibody may themselves be used in an anti-cancer treatment or in a diagnostic method. Thus the invention also provides such an antibody or fragment thereof for use in a method for treatment of the human or animal body by surgery or therapy or in a diagnostic method practised on the human or animal body,-such as in anti-cancer therapy. The invention also provides use of such an antibody or fragment thereof in the production of a pharmaceutical composition for use in such a method.

The invention provides a pharmaceutical composition containing such an antibody or fragment thereof and a diluent or carrier therefor. The invention also provides a method of diagnosing or treating cancer by administering an effective non-toxic amount of such an antibody or fragment thereof to a human or non-human animal in need thereof.

The invention provides the use of H3 chain of SM3 as a therapeutic or diagnostic agent. The invention also provides the use of Hi chain of SM3 as a therapeutic or diagnostic agent. Thus the invention also provides such an H3 or HI chain for use in a method for treatment of the human or animal body by surgery or therapy or in a diagnostic method practised on the human or animal body, such as in anti-cancer therapy. The invention also provides use of such an HI or H3 chain in the production of a pharmaceutical composition for use in such a method.

The invention provides a pharmaceutical composition WO 99/10379 PCT/GB98/02542 -22containing such an HI or H3 chain and a diluent or carrier therefor. The invention also provides a method of diagnosing or treating cancer by administering an effective non-toxic amount of such an H1I or H3 chain to a human or non-human animal in need thereof.

The invention provides the use of the structure factors and/or structural coordinates to solve structural coordinates of other crystals. Such a crystal may comprise an antibody or antibody fragment. In particular the structural coordinates can be used to solve the structural coordinates of a crystal comprising an antibody which has a non-proline cis peptide bond. The cis peptide bond may be in the H3 chain of the antibody.

The invention provides the use of the structure factors and/or structural coordinates to engineer, design or modify an antibody. The engineering may be for the purpose of humanising the antibody. The engineering may comprise the replacement of portions of- the antibody. The portions of the antibody may be replaced with portions from another protein, such as a human protein, for instance a human antibody. Two dimensional and three dimensional representations, such as those discussed previously, may be used during the engineering of the antibody to ensure that the epitope binding site of the antibody is the same or substantially similar to the antibody binding site of SM3. The engineering of the antibody may be for the purpose of increasing the contribution made by the H3 and HI chains in the binding of the epitope.

The invention provides the use of an engineered glycine in a protein to insert a non-proline cis peptide bond into the protein. The insertion of the glycine may enable the protein to undergo conformational change, for instance in connection with a specific binding reaction where the affinity, avidity or selectivity of the WO 99/10379 PCT/GB98/02542 -23specific binding reaction is modified by adoption of a cis peptide bond adjacent to the engineered glycine. The engineered glycine can be inserted using site directed mutation techniques, such as those described in Short Protocols in Molecular Biology, 3rd edition, published by John Wiley and Sons, Inc., USA. The protein may be an antibody or fragment of a antibody. The engineered glycine may be in a CDR loop of the antibody. The insertion of the engineered glycine in an antibody will generally affect the binding of the antibody to an epitope.

The invention also provides a method of producing a crystal which comprises the use of cadmium. Generally the method comprises contacting any one of the moieties to be crystallised with cadmium such as by use of a solution of a cadmium salt. The cadmium ions may be present in the solution in which the crystal is grown.

In the case where the mimic of SM3, the mimic of the MUCI epitope or the specific binding agent comprise a peptide then such agents may be delivered to animal or human by the admimistration of a nucleic acid which encodes such a peptide. Transcription and translation or merely translation of the nucleic acid would lead to the production of the peptide in vivo. It is appreciated by the skilled artisan that the nucleic acid may be within a suitable vector, especially an expression vector, for instance a virus or an organism which is administered, such as a Vaccinia virus, for instance an attenuated Vaccinia virus or the nucleic acid may be administered in the presence of a suitable diluent or carrier as in the use of "naked DNA". Nucleic acids encoding such peptides form a further aspect of the present invention as do their uses in cancer therapy and pharmaceutical compositions containing them.

Thus the invention also provides such nucleic acids WO 99/10379 PCT/GB98/02542 -24for use in a method for treatment of the human or animal body by surgery or therapy or in a diagnostic method practised on the human or animal body, such as in anticancer therapy. The invention also provides use of such nucleic acids in the production of a pharmaceutical composition for use in such a method. The invention provides a pharmaceutical composition containing such nucleic acids and a diluent or carrier therefor. The invention also provides a method of diagnosing or treating cancer by administering an effective non-toxic amount of such nucleic acids to a human or non-human animal in need thereof.

The mimic of SM3, mimics of the MUCI epitope, selective binding agents, nucleic acids, viruses or organisms containing nucleic acids of the invention (hereafter referred to as substances of the invention) may be formulated for clinical administration by mixing them with a pharmaceutically acceptable carrier or diluent. For example the substances can be formulated for topical, parenteral, intravenous, intramuscular, subcutaneous, or transdermal administration. They may be mixed with any vehicle, e.g. a diluent or carrier which is pharmaceutically acceptable and appropriate for the desired route of administration. The pharmaceutical carrier or diluent for injection may be, for example, a sterile or isotonic solution such as Water for Injection or physiological saline.

The dose may be adjusted to deliver an effective non-toxic amount and according to various parameters, especially according to the nature and efficacy of the substance used; the age, weight and condition of the patient to be treated; the mode of administration used; the conditions to be treated; and the required clinical regimen. As a guide, the amount of therapeutic substance such as a polypeptide to be administered by injection WO 99/10379 PCT/GB98/02542 will generally be from 10 to 10OOpg. For instance 100 to 500pg. For in vivo diagnostic imaging purposes in particular, the dose will depend on similar factors but may need to be much larger in order to generate an appropriate image.

The routes of administration and dosages described are intended only as a guide since a skilled practitioner will be able to determine readily the optimum route of administration and dosage for any particular patient and condition.

The substances of the invention may be produced by conventional techniques well known to those skilled in the relevant arts. Peptides may be synthesised de novo or produced by transcription and translation of DNA or translation of RNA in a suitable expression system by conventional methods. Nucleic acids may be produced by de novo synthesis, obtained from natural sources such as by conventional probing and cloning techniques or generated from natural sources by modification by well known methods. Antibodies may be made by suitable immunisation protocols and purified from immunised animals by conventional techniques, or they may be made by hybridomas and similar antibody secreting cell lines cultured in vitro or they may be obtained by expression from suitable nucleic acids. Hybridomas and other antibody secreting cells may be obtained, cultured and used to produce antibodies by conventional methods.

Chemical modification of such materials as peptides and antibodies may be achieved by well known methods.

Fragments of antibodies may be produced by known chemical or enzymatic digestions or by expression from suitably modified nucleic acids. New chemical entities such as mimics of the MUC1 epitope may be produced by the well known techniques of synthetic organic chemistry.

The substance of the invention does not include WO 99/10379 PCT/GB98/02542 -26those peptides disclosed in WO-A-88/05054 or in WO-A- 90/05142.

The present invention is illustrated by the figures of the accompanying drawings which are described below: Brief Description of the Drawings Figure 1 shows the amino acid sequence of the MUC1 tandem repeat.

Figures 2 and 3 show experimental electron density maps and the refined atomic models of the epitope binding site of SM3 and part of the crystal peptide.

Figure 4 shows a comparison of the conformations of the unbound and bound peptide.

Figures 5 and 6 show molecular surface features of the SM3-crystal peptide interaction.

Figure 7 is a stereo view of the non-proline cispeptide bond in CDR H3.

Figures 8, 9, 10 and 11 are LIGPLOTs of the peptide binding site.

Figure 12 shows experimental density maps of the cis- peptide conformation in H3.

Figure 13 shows a Ramachandran plot for the H3 fragment.

Figure 14 shows the main chain temperature factors of the fragment from H3.

Figure 15 shows a stereo view of the MUC1 peptide in the antibody combining site.

Figure 16 shows a stereo view of the non-proline cis- peptide bond in H3.

Detailed Description of the Drawings Figure 1 shows MUC1 tandem repeat sequence written from N- to C-terminal using the Internationally recognised 3-letter code (which is used throughout this specification). The epitope recognised by SM3 is shown in WO 99/10379 PCT/GB98/02542 -27bold (Pro-Asp-Thr-Arg-Pro) with the immunodominant region indicated by the double headed arrow. The probable glycosylation sites are shown in bold italics. The peptide used for the crystallisation studies (Thr-Ser- Ala-Pro-Asp-Thr-Arg-Pro-Ala-Pro-Gly-Ser-Thr) is underlined (and is herein referred to as "the crystal peptide").

Figures 2 and 3 show experimental electron density maps and refined atomic models calculated using the observed structure factors (30 to 1.95 A) and calculated phases after solvent modification. The maps are contoured at 1.0 o. Figure 2 shows part of the MUC1 peptide antigen showing the immunodominant region. The numbering refers to Figure 1. Figure 3 shows the cispeptide bond in CDR H3 between residues Gly96H and Gln97H. Two water molecules are shown forming hydrogen bonds to amide nitrogens.

Figure 4 shows the unbound and bound peptide. The unbound peptide is shown on the left. The structure represents the "knob-like" region and was determined in solution by NMR; it includes the whole of one tandem repeat and parts of the two flanking repeats (Fontenot et al., 1995). The conformation of the crystal peptide as bound by SM3 is shown on the right. There appears to be a conformational transition of the "knob-like" region upon SM3 binding, which leads to a more extended peptide conformation. The main differences can be attributed to the angles of Asp5P and Arg7P.

Figure 5 shows a CPK model of the SM3 combining site with the individual CDR loops labelled. The crystal peptide is shown contacting all of the CDR's except H2.

Figure 6 shows electrostatic surface potential representation of the SM3 peptide complex. The surface was calculated using GRASP (Nicholls et al., 1991). The crystal peptide is shown as a stick model.

WO 99/10379 PCT/GB98/02542 -28- Figure 7 shows the cis-peptide bond in H3. The interactions between the residues Gly96H-Gln97 and the crystal peptide (solid) are shown. Hydrogen bonds are dotted (drawn using MOLSCRIPT; Kraulis, 1991).

Figures 8, 9, 10 and 11 are LIGPLOTS showing the main interactions which occur between the SM3 binding site, the crystal peptide and water molecules.

KEY:

Ligandm/c His 53 Non-ligand residues involved in hydrophobic Ligand sidechain contact(s) Hydrogen bond and its length Corresponding atoms involved in hydrophobic contact(s) WAT water Figure 12 shows experimental electron density maps calculated using the observed structure factors (30 to 1.95 A and calculated phases after solvent modification, contoured at 1.0 o level (2Fo-Fc) and 2.0 o (Fo-Fc).

Residue numbering as in the text. The model with this cis- peptide bond is coloured according to atom type.

2Fo-Fc difference density, calculated for the refined model with a trans Gly96H-Gln97H peptide bond. 2Fo- Fc and Fo-Fc (residual negative electron density; and positive density) map, calculated for the refined model with a cis Gly96H-Gln97H peptide bond. 2Fo-Fc difference electron- density map around the final cis Gly96H-Gly97H fragment, showing the hydrogen bonds which appear to stabilise the cis peptide conformation.

Figure 13 shows a Ramachandran plot for the H3 fragment refined with cis and trans. Gly96H-Gly97H peptide bond. Residues are labelled accordingly. Created by PROCHECK, Laskowski et al., 1993.

Figure 14 shows the main chain temperature factors of the fragment from H3 which contains the non-proline cis- peptide bond between Gly96H and Gln97H. Values for WO 99/10379 PCT/GB98/02542 -29the refined cis confirmation are shown as open boxes (solid line), while those for the trans are indicated with closed circles (dashed line).

Figure 15 shows a view of the MUC1 peptide in the antibody combining site. The peptide antigen is labelled and is shown in bold. SM3 Fab residues which interact with the peptide are labelled. Hydrogen bonds are shown as dotted lines with water molecules as black spheres.

Drawn by MOLSCRIPT (Kraulis, 1991).

Figure 16 shows the cis peptide bond. The interactions between the residues Gly96H-Gln97H and part of the peptide antigen (bold) are shown. Hydrogen bonds are dotted and waters are represented as black spheres (drawn using MOLSCRIPT; Kraulis, 1991). The hydrogen bond between Gly96H and the peptide antigen, as mediated via a water molecule, is lost for a trans peptide conformation for Gly96H-Gln96H.

The invention .is further illustrated by the Examples: Example 1 Assessment of the Binding of the MUC1 epitope to SM3.

The sequence of the MUC1 peptide in the context of the MUC1 repeat is shown in Figure 1. The region of the MUC1 repeat for the co-crystallisation studies was chosen to keep the peptide as soluble as possible, while maintaining most of the tertiary structure of the knob region as based upon the NMR structure of the mucin repeats [Fontenot, Mariappan, Catasti, P., Domenech, Finn, O.J. and Gupta, G.J. Biomol. Struct.

and Dynam. 13, (1995) 245-260]. The binding of the MUC1 epitope to SM3 was assessed by inhibition in an ELISA assay. The assay involved SM3 binding to a recombinant fusion protein containing seven copies of the MUC1 tandem repeat, a lug/ml concentration of SM3 was incubated with WO 99/10379 PCT/GB98/02542 increasing concentrations of peptide, a 50% inhibition was achieved at a peptide concentration of approximately (Apparent Ka~24pM). In contrast a peptide of the same composition but different sequence (Ala-Arg-Pro-Thr- Gly-Thr-Ser-Asp-Pro-Thr-Pro-Ala-Ser) gave no detectable inhibition at the same concentration.

Example 2 Preparation of the SM3 Fab fragments.

SM3 at 4mg/ml in 100 mM sodium acetate pH 6.0, 3mM EDTA, 50mM cysteine was incubated with 160 pg/ml of papain for 4 hr at 37 0 C. Fabs were purified by gel filtration on Superose 6 in PBS, followed by dialysis into 20mM Tris pH 8.0 and then Mono Q ion exchangechromatography. Fractions were analyzed by SDS PAGE and Fab fractions concentrated to 4 mg/ml in 10mM Tris pH The overall yield was 22%.

Example 3 Crystallisation of the SM3 Fab fragment bound to the MUC1 epitope.

The SM3 Fab fragments were mixed with concentrated solution of the peptide at a molar ratio 1:5, incubated for 3 hours at 37 0 C, and then concentrated to 9.5 mg/ml.

The crystallisation trials were conducted using the hanging drop method. A wide range of conditions were tested using commercial screens, namely Hampton Research I and II [Jancarik, J. and Kim, S.H. J. Appl. Cryst. 24, (1991) 409-411 and Cudney, Patel, Weisgraber K., Newhouse, and McPherson, A. Acta Cryst. D50, (1994) 414-423]. Although the initial screens did not give crystals, they indicated that polyethylene glycol (PEG) was the most promising precipitant. In subsequent trials we varied the molecular weight of PEG, buffer pH range and effect of salts. Finally, a shower of tiny needles appeared in the drops equilibrated against a solution of PEG 4000 as a precipitant and acetate buffer, WO 99/10379 PCT/GB98/02542 -31pH 5.0-7.0, with aggregated prisms appearing at higher pH, 6.5-7.5. However, all of these original crystals were too small for data collection. As seeding attempts were unsuccessful, we tried other ways to improve the crystal morphology and size, including a metal ion screen. Addition of cadmium chloride gave larger crystals which were often twinned or aggregated.

However, occasionally single crystals could be separated, one of which was used for data collection. The final conditions were; 2.5pl of the antibody-antigen complex mixed with 2.5pl of the well solution containing 0.2 M CdCl 2 19% w/v of PEG 4000, and 0.1 M acetate buffer, pH Example 4 Diffraction measurements of the SM3 Fab fragment/MUC1 epitope crystal.

A monocrystal of dimensions 0.4 x 0.2 x 0.03 mm was used for the diffraction measurements at the X11 outstation of the DESY synchrotron in Hamburg. Analysis of the diffraction data showed that the crystal belongs to the monoclinic P2 1 space group with unit cell dimensions a=42.2, b=83.9, c=64.5 A, and 0=93.4.

Assuming one complex molecule per asymmetric unit, the specific volume V,=2.50 A 3 /Da of protein corresponds to a solvent content of 51% (Matthews, 1968). Since the number of available crystals was limited, data collection was carried out at 110 K. The crystal was transferred to a glycerol-enriched mother liquor (10% of the water in mother liquor was substituted by glycerol) and then flash-frozen using standard techniques (Teng, 1990) in a stream of nitrogen gas produced by an Oxford Cryosystem.

A complete dataset up to 1.95 A resolution was collected using synchrotron radiation at wavelength 0.912 A (Table The data was collected in 1.00 oscillation frames over 1800 oscillation range on an 18cm MAR Research image WO 99/10379 PCT/GB98/02542 -32plate from a single crystal. The frames were processed with DENZO software (Otwinowski, 1993) resulting in 111,363 observations with I>1.0 Further scaling with the CCP4 suite gave 33,093 independent reflections with Rmerge of 6.9%.

Example 5 Structure Determination and Model Refinement.

The CCP4 package [Collaborative Computational Project, No. 4 Acta Crystallogr. D50, (1994) 760-763].

was used for all crystallographic calculations unless otherwise stated. The structure of the SM3-MUC1 pept'ide complex was solved by the Molecular Replacement method as implemented in the program AMoRe [Navazza, J. Acta Crystallogr. A50, (1994) 157-163], using the Murine SE155-4 Fab fragment complexed with the dodecasaccharide [Cygler, Rose, D.R. and Bundle, D.R. Science 253, (1991) 442-445] as a search model. A consistent solution for the rotation and translation function was obtained only after removing the bound antigen, CDRs and N- and Ctermini. Replacing all non-conserved residues with alanines and performing rigid body refinement with X-PLOR .[Brunger, A.T. (1992) X-PLOR, A System for Crystallography and NMR (Yale Univ. Press, New Haven, CT) Version 3.1] resulted in a crystallographic R-factor of with R-free of 49% as calculated against a randomly selected set of reflections [Brunger, A.T. Acta Crystallogr. D49, (1993) 24-36]. At this stage, several omit maps were calculated covering the whole molecule, and the model was manually rebuilt using the program 0 [Jones, T.A. and Kjeldgaard, M. (1994) 0 The Manual.

Uppsala University, Sweden]. Further refinement of the model was performed with the standard X-PLOR simulated WO 99/10379 PCT/GB98/02542 -33annealing protocol with resolution cut-off at 3.0 A, followed by manual rebuilding with 0 and Turbo-Frodo [A.

Russel and C. Cambillau, Marseille, France]. The Rfactor converged to 34% (R-free 43%) and substantial, continuously positive, electron density close to the CDRs became visible which corresponded to residues 2-10 of the peptide. The peptide was built into the density and further alternative rounds of refinement, DM solvent modification [Cowtan, K. Protein Crystallography 31, (1994) 34-38] and manual rebuilding was carried out using REFMAC as implemented in the CCP4 package and X-PLOR, gradually increasing the resolution to 1.95 A.

Inspection of the 2Fo-Fc and Fo-Fc difference Fourier maps showed significant positive electron density corresponding to eight cadmium ions and a large number of solvent molecules. Several iterative refinement cycles were carried out, and the water and cadmium positions were checked after each cycle. All atoms were refined with individual isotropic B-factors. The Engh-Huber parameters [Engh, R.A. and Huber, R. (1991) Accurate bond and angle parameters for X-ray protein structure refinement. Acta Crystallogr. A47, 392-400] as used in X-PLOR were altered to allow the Gly96H-Gln97H bond to adopt a cis conformation. No electron density was visible for residues 128-133 of heavy chain as well as some terminal residues (L2, L209-212, H214, P1 and P11- 13). For the same reason residues Asp41L, Glul23L, Gln163L, GlnlH, Glu42H, Glu61H, Glu85H, Serl34H, Serl72H, Aspl73H, Ser203H, Lys208H and Ser2P were modelled as Alanines. The final model contains 3227 atoms including the peptide, 333 water molecules, two chlorine and eight cadmium ions and the final refinement statistics are shown in Table 4. The overall quality of the model was checked with PROCHECK program. [Laskowski, MacArthur, Moss, D.S. and Thornton, J.M. J.

WO 99/10379 PCT/GB98/02542 -34- Appl. Crystallogr. 26, (1993) 283-291]. Buried contact surface areas were calculated with the program PDBAREA [Lee et al.J. Mol. Biol (1971), 55, 379-400 It was noted that during the refinement and manual rebuilding procedures, some of the SM3 primary sequence was incorrect. A cDNA corresponding the SM3 Fab region was sequenced confirming the errors in the SM3 sequence.

The peptide was unambiguously built into the electron density from difference Fourier maps. Since the MUC1 peptide is almost symmetrical, it was necessary to confirm the correct orientation for the peptide in the electron density. This was done by modelling the peptide backwards which resulted in a poorer fit into the density, and a higher R-Free and crystallographic Rfactor after one round of refinement.

The correctness of the cis-bond was confirmed by trying to refine it as a trans-bond. This resulted in a significant increase in main chain B-factors for Gly96H and subsequently poor quality electron density maps in this region (data not shown). In addition, some potential hydrogen bonds between the peptide and antibody are not possible if the peptide bond is in trans conformation. Unrestrained refinement using REFMAC (CCP4, 1994) always resulted in a cis-conformation for the Gly96H-Gln97H peptide bond, the electron density for which is shown in Figure 3.

Example 6 The SM3 Fab fragment/MUC1 epitope structure.

The structure of the SM3-peptide antigen complex has revealed a number of unexpected and new insights into how antibodies recognise peptide antigens. In particular CDR loop H3 contains a non-proline cis-peptide bond. The structure of the SM3 fab fragment/MUCl epitope was checked to a resolution of 1.95 A. All of the residues WO 99/10379 PCT/GB98/02542 of the epitope lie within favoured regions of the Ramachandran plot (data not shown) except for two residues (Thr51L, Ser93L) on CDRs (L2 and L3), both of which are involved in interactions with the bound peptide. The individual atomic B-factors are within reasonable limits (average 16.3A 2 showing higher values only in residues located on mobile loops or solventexposed fragments (data not shown). The quality of the density corresponding to nine residues of the MUC1 peptide antigen is shown in Figure 2A. The peptide residues have average atomic B-factors of 15.3A 2 indicating that the observed peptide is well ordered.

There are eight cadmium sites in the SM3-peptide, five with full occupancy, and three with relative occupancy of 0.75. They are mainly making contacts with the nitrogen atoms of histidines and carboxylic group of Glu or Asp residues between symmetry related molecules and/or chains (data not shown). All have distorted octahedral co-ordination completed by bound waters and chloride ions. It appears that the cadmium ions stabilise contacts between chains or molecules and contribute to the crystal packing since crystallisation in the absence of cadmium produces tiny needles, too small for diffraction experiments. The SM3-cadmium structure is an unusual example of a crystal structure in which cadmium ions were introduced directly and not simply by replacing other bound metal ions.

SM3 MUC1 peptide antigen interactions The MUC1 peptide forms two intra-peptide hydrogen bonds: Pro 4 (atom O) to Thr 6 (atom N) and Asp 5 (atom OD1) to Arg 7 (atom N).

The MUC1 peptide sits in an elongated groove of the SM3 antibody and is surrounded by.all six CDR loops The peptide is anchored by the electrostatic interactions WO 99/10379 PCT/GB98/02542 -36of Asp5P and Arg7P and is bound to the SM3 antibody primarily by hydrophobic contacts (Table All six CDRs of the SM3 antibody participate to some degree in the MUC1 peptide binding, although of the residues on the H2 chain only Arg52H makes contact with the peptide, and this through a water mediated interaction. The major contribution to antigen binding comes from HI, of which three residues Asn31H, Tyr32H, Trp33H are making contacts with seven residues of the peptide (Table These interactions cover 38% of the total CDRs surface area which is buried upon antibody-peptide binding, and are mainly hydrophobic, although there are some hydrogen bonds and salt bridges. The cis-peptide bond between Gly96H and Gln97H plays a crucial role in antigen binding (Table The nitrogen atom of Gly96H forms hydrogen bonds with both the carbonyl oxygen of Asp5P and the OD2 carboxyl group via a water molecule. The hydrophobic part of the Gln97H side chain interacts with Pro4P which is oriented between Trp33H (HI) and Tyr32L Pro4P also stacks against Trp91L making Pro4P the most buried residue of the whole peptide antigen. The polar headgroup of Gln97H hydrogen bonds directly with residues of LI, L2 and Asp5P. The important antigenic residue Arg7P interacts with Tyr32H (H1) and Asn31H (HI) whilst the C-terminal residues of the peptide sit in a hydrophobic pocket surrounded by Pro56L Phe27H (HI) and Tyrl02H In summary, there are a number of direct water-mediated hydrogen bonds between the peptide and antibody (Table The rest of the SM3-peptide interactions are primarily hydrophobic.

Hydrophobic contacts are dominant at the SM3 antibody combining face since out of a total 185 A2 antigen-antibody contact area, 128 A2 is covered by hydrophobic interactions (Table A similarly high ratio is also observed for the peptide antigen where 66% WO 99/10379 PCT/GB98/02542 -37of the buried surface area (total 603 A2 is represented by non-polar residues. Such high ratios would suggest that hydrophobic interactions are the main driving force in SM3-peptide complex formation. The average Fab provides space for binding about 10 residues of peptide antigen, leaving the rest highly mobile and hence very often disordered and unobserved in electron density maps.

There is a clear surface complementarity between the SM3 antibody and peptide antigen. Of particular interest is the surface complementarity around Pro4P which appears to be facilitated by the presence of the cis-peptide bond within H3 (see later).

A fragment search against a library of all antibody structures deposited in the Brookhaven database (Bernstein et al., 1977) was unable to find a suitable replacement for H3. The best solution of the search, which used distances across the base of H3, placed the fragment Ca atoms at 2.6 A root mean squared separation from the equivalent crystal structure co-ordinates of H3.

However, it is well known that conformations of CDR H3 are difficult to classify and predict (Reczko et al., 1995; Shirai et al., 1996). In the SM3-peptide antigen structure, residues from CDRs HI and to a lesser extent H3 are the major contributors to the binding of peptide antigen (Table This is in contrast to other antibody-peptide complexes where L3 and H3 (MacCallum et al., 1996) or H2 and H3 (Stanfield and Wilson, 1993) are the main contributors to antigen binding. One obvious conclusion from this is that it would be difficult to predict, without a crystal structure of a complex, the expected contributions of each of the CDRs to peptide antigen binding.

The presence of non-proline cis-peptide bonds within proteins is very rare with an estimated 0.05% of known protein structures containing such bonds (Stewart WO 99/10379 PCT/GB98/02542 -38et al., 1990; Herzberg and Moult, 1991). To our knowledge, the SM3-peptide complex represents the first such example in a hypervariable loop region of an antibody combining site. Non-proline cis-peptide links have however, been found in the active sites of a number of hydrolases (Perrakis et al., 1994). In these examples, the cis-peptide conformation is probably involved in facilitating contact and/or recognition of the substrate (Perrakis et al., 1994). Interestingly, to date, all of the antibody-peptide structures contain a cis-proline residue within CDR L3, which is important for peptide-antigen binding. The reasons for the conservation of the cis-Pro is unclear, although it is interesting that the two residues on either side of the cis-Pro, make at least one direct peptide contact and a second indirect contact, via other residue of the CDRs.

The SM3 structure however, does not contain the equivalent proline in L3, but appears to have the cispeptide bond, albeit non-proline, on the opposite side of the antibody combining face in H3. At least two conclusions can be drawn from these observations: A cis-peptide bond within the antibody-antigen combining site is an important and common feature of peptideantigen binding; The SM3-peptide complex differs from all other antibody-peptide complexes in that the cispeptide bond is non-proline and is located in another CDR loop. As to the role of the cis-peptide bond, it may relate to specific interactions with the hydrophobic surface on the peptide antigen. An additional reason for this bond to be cis rather than trans, may be due to the small size of H3 resulting from the extended peptide antigen epitope running across its upper surface. A small all-trans CDR would have less degrees of freedom to accommodate such a change.

WO 99/10379 PCT/GB98/02542 -39- Comparison of bound and unbound MUCI peptide antigen A comparison of the SM3 bound MUC1 peptide with the unbound solution structure obtained from NMR studies of three MUC1 repeats (Fontenot et al., 1995) is shown in Figure 4. The structure of the core region within each repeat in the solution structure is different to that of the antibody-bound peptide antigen. The overall geometry of the "knob-like" protrusion has changed from two consecutive type II B-turns as observed in solution (Fontenot et al., 1995) to that of an essentially extended geometry when bound to the SM3 antibody. There are differences in all of the phi and psi torsion angles between the bound and unbound peptide, with the main differences centred on the phi angles of Asp5P and Arg7P, which together make a significant percentage of the total peptide-contacts (Table 4).

This rearrangement could keep the charged head groups partially solvated on antibody binding, thereby presenting a predominantly hydrophobic surface to the SM3 antibody combining site. Thus, if the NMR structure of the MUC1 repeats represents the most prominent conformation in vivo (Fontenot et al., 1995), then the SM3 antibody induces a conformational change in the mucin molecule upon binding, at least within the region of the peptide epitope. This would suggest that SM3-peptide recognition is by an "induced fit" mechanism.

P:\OPER\Fas\87 I -9-spe.doc- /1106/02 39A Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

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Burchell, Gendler, Taylor-Papadimitriou, Girling, Lewis, Millis, R. and Lamport, D. (1987) Development and characterisation of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Cancer Res. 47, 5476-5482.

Burchell, Taylor-Papadimitriou, Boshell, Gendler, D. and Duhig, T.

(1989) A short sequence within the amino acid tandem repeat of a cancer associated mucin, contains immunodominant epitopes. Int. J. Cancer 44, 691-696.

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WO 99/10379 PCT/GB98/02542 -46- Table 1 Structure factors of the SM3 fragment/crystal peptide crystal which is described in the Examples This table is shown below. The data is arranged in four separate columns as below. Each row of a column consisting of five numbers describes the results of a single reflection. Reading left to right, the first three numbers represent h, k and 1 respectively and are the crystallographic reflection indices. The fourth number represents the structure factor F(hkl) defined as the computed sum of the Fourier series for each reflection hkl. As multiple measurements are made of the same reflection a standard deviation for each structure factor has been provided as the fifth number in the row.

Tables 2a and 2b Structure (atomic coordinates) of the SM3 fragment/crystal peptide crystal which is described in the Examples These tables are shown below. The top row, called CRYST1, defines the spacegroup and crystal cell dimensions. Scale 1, Scale 2 and Scale 3 define an orthogonalisation matrix which when applied to the individual coordinates puts them into an orthogonal axis system i.e. 90 degrees between each of the axes x, y and z.

Below these rows reading left to right the second row gives the chemical symbol of the atom. OH2 represents a water molecule. The letter following indicates the position of the atom in the amino acid residue using a convention recognised by a skilled partisan. The letter refers to the equivalent Greek symbol A for alpha, WO 99/10379 PCT/GB98/02542 -47- B for beta etc.). The third column gives the identity of the residue in which the atom is present. WAT represents a water molecule. The fifth column gives the number of the amino acid in the protein. The sixth, seventh and eighth columns give the spatial position of the atom as x, y and z coordinates respectively. The ninth column shows the occupancy of that atom which will be 1.0 for present and 0.0 for absent not observed) and the tenth column gives the B-factor which refers to the mobility.

WO 99/10379 WO 9910379PCT/GB98/02542 Table 1.

-21 0 -21 0 -21 0 -21 0 -21 0 -21 0 -21 0 -21 0 -21 0 -21 0 -21 1 -21 1 -21 1 -21 1 -21 1 -21 1 -21 1 -21 1 -21 1 -21 2 -21 2 -21 2 -21 2 -21 2 -21 2 -21 2 -21 2 -21 2 -21 2 -21 3 -21 3 -21 3 -21 3 -21 3 -21 3 -21 3 -21 3 -21 3 -21 4 -21 4 -21 4 -21 4 -21 4 -21 4 -21 4 -21 4 -21 4 -21 5 -21 5 -21 5 -21 '5 -21 5 -21 5 -21 5 -21 5 -21 5 -21 6 -21 6 -21 6 -21 6 -21 6 -21 -21 -21 -212 -21 -21 -21 -21 -21 1 132.8 9.3 2 172.8 12.6 3 124.7 10.3 4 183.9 7.7 5 160.3 19.4 6 152.0 14.3 7 87.1 11.0 8 96.3 9.2 9 41.4 19.9 10 114.6 15.0 1 22.8 11.0 2 109.3 11.7 3 46.8 18.7 4 58.2 13.4 5 102.7 10.0 6 21.7 10.7 7 60.1 12.3 8 73.2 7.8 10 95.2 18.3 1 63.4 12.1 2 77.5 17.8 3 42.2 15.8 4 117.3 10.0 5 73.3 15.1 6 89.8 10.2 7 54.3 12.8 8 18.0 9.0 9 36.7 14.5 10 109.9 13.3 1 75.6 9.7 2 77.7 18.4 3 32.4 13.9 4 34.7 13.7 5 42.5 14.0 6 173.0 6.9 7 67.2 11.0 8 104.2 5.9 9 37.4 14.8 1 30.9 13.4 2 21.8 10.5 3 76.4 10.8 4 149.5 6.1 5 24.9 11.7 6 41.2 15.4 7 53.1 15.6 8 93.8 9.6 9 22.2 10.7 1 27.8 13.0 2 113.4 11.7 3 44.4 18.1 4 54.6 16.2 5 64.2 13.2 6 152.4 10.5 7 107.0 22.2 8 26.8 12.0 9 117.3 5.8 1 87.8 8.1 2 41.2 15.9 3 90.2 11.7 4 81.2 8.7 6 62.7 13.0 7 23.2 11.6 8 47.6 13.1 11 132.5 12.4 12 71.7 10.6 7 3 153.7 7.8 7 4 44.0 15.4 7 5 57.1 11.3 7 6 68.6 9.3 7 7 34.3 13.8 7 8 59.1 17.2 -21 8 1 50.2 16.3 -21 8 2 46.7 13.3 -21 8 3 30.7 13.4 -21 8 4 134.5 7.9 -21 8 5 89.1 7.5 -21 8 6 45.5 13.4 -21 8 7 28.3 14.1 -21 9 2 34.4 14.6 -21 9 3 119.1 6.5 -21 9 5 118.5 6.9 -21 9 6 85.0 13.0 -21 10 1 126.7 13.0 -21 10 2 113.5 11.6 -21 10 3 30.0 13.8 -20 0 2 112.0 9.3 -20 0 3 42.6 19.1 -20 0 4 35.9 24.8 -20 0 5 46.1 28.7 -20 0 6 19.5 13.6 -20 0 7 110.2 9.1 -20 0 8 111.9 6.9 -20 0 9 169.2 5.9 -20 0 10 156.5 6.8 -20 0 11 18.3 13.1 -20 0 12 176.6 6.8 -20 0 13 31.9 17.7 -20 0 14 48.5 18.8 -20 1 1 71.0 11.0 -20 1 2 28.6 12.6 -20 1 3 102.6 6.4 -20 1 4 137.5 13.5 -20 1 5 85.8 20.6 -20 1 6 101.1 7.9 -20 1 7 104.1 6.3 -20 1 8 86.4 7.4 -20 1 9 39.8 13.3 -20 1 10 62.3 14.0 -20 1 11 141.0 5.5 -20 1 12 18.8 9.1 -20 1 13 179.3 8.7 -20 1 14 54.1 13.8 -20 2 1 41.6 16.7 -20 2 2 62.9 13.2 -20 2 3 65.6 12.3 -20 2 4 73.6 22.9 -20 2 5 61.2 22.0 -20 2 6 51.8 15.1 -20 2 7 26.5 12.0 -20 2 8 144.3 4.6 -20 2 9 88.2 6.5 -20 2 10 40.1 14.6 -20 2 11 94.4 10.7 -20 2 12 28.5 12.1 -20 2 13 147.0 4.8 -20 2 14 151.0 4.7 -20 3 1 78.7 14.1 -20 3 2 87.6 7.8 -20 3 3 51.3 13.6 -20 3 4 106.2 11.4 -20 3 5 92.5 11.6 -20 3 6 36.9 13.6 -20 3 7 143.2 6.8 -20 3 8 82.7 7.3 -20 3 9 20.2 9.6 -20 3 11 125.4 5.7 -20 3 12 63.0 8.5 -20 3 13 127.1 7.6 -20 3 14 55.1 13.6 -20 4 1 108.5 9.5 -20 4 2 60.3 12.0 -20 4 3 33.2 13.2 -20 4 4 104.1 7.3 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -20 -2( -2( -2( -2( -2( -24 -21 -24 -24 -2' -2' -2 -2 -2 -2 -2 4 5 40.9 14 4 6 118.7 4 7 49.1 1~ 4 8 74.8 6 4 9 39.5 1: 4 10 181.5 4 11 137.8 4 12 88.2 4 13 151.8 4 14 31.1 1 5 1 89. 18 5 2 36.5 1 5 3 98.3 7 5 4 19.0 9 5 5 168.0 5 6 106.6 5 8 95.6 5 9 88.32 5 10 170.3 5 11 92.9 5 12 63.6 5 13 114.7 5 14 24.0 6 1 70.6 1 6 2 29.0 1 6 3 112.6 6 4 99.3 6 5 99.5 6 6 190.6 6 8 43.7 1 6 9 112.5 6 10 69.2 6 11 141.8 6 12 66.2 6 13 84.8 6 14 190.8 7 1 173.9 7 2 111.4 7 3 59.0 7 4 125.5 7 5 186.8 7 6 96.2 7 7 189.9 7 8 21.3 7 9 110.5 7 10 89.4 7 11 51.7 7 12 130.5 7 13 33.8 48 1 179.9 48 2 171.7 I8 3 223.0 48 4 83.0 48 5 23.5 8 6 98.3 8 7 46.7 8 8 67.9 8 9 90.5 8 10 88.8 )8 11 97.2 0 8 12 45.0 0 8 13 96.2 0 9 1 58.1.

0 9 2 126.0 01 9 3 153.5 0 9 4 86.1 0 9 5 25.9 0 9 7 35.8 0 9 8 100.4 0 9 10 62.6 0 9 11 74.7 0 9 12 23.0 6.3 41.0 .8 2.9 6.0 5.3 6.2 5.7 2.9 1.7 4.5 ~.1 4.4 5.4 7.0 1.4 5.3 7.3 13.0 5.0 10.9 4.9 2.8 7.5 8.2 6.7 7.1 3.0 6.2 9.3 5.1 12.1 6.7 7.0 9.1 14.2 17.7 7.5 4.8 7.6 11.2 10.7 6.9 6.8 12.3 6.0 12.7 8.5 8.0 8.0 8.6 11.0 6.1 16.9 11.0 7.2 6.9 6.0 13.3 7.2 11.6 6.2 6.9 10.8 11.6 13.2 7.0 9.3 7.7 10.9 -20 10 1 35.7 13.5 -20 10 2 25.4 11.6 -20 10 3 89.3 7.8 -20 10 4 44.2 16.7 -20 10 5 39.8 14.3 -20 10 6 27.9 12.9 -20 10 7 21.4 10.2 -20 10 8 70.8 10.1 -20 10 9 76.1 8.8 -20 10 10 54.9 13.8 -20 10 11 21.7 10.2 -20 10 12 72.9 9.1 -20 11 1 138.6 10.6 -20 11 2 107.6 6.4 -20 11 3 62.9 14.6 -20 11 4 152.7 10.5 -20 11 5 92.7 11.1 -20 11 6 94.9 13.5 -20 11 7 74.5 8.1 -20 11 8 104.8 5.7 -20 11 9 103.8 5.7 -20 11 10 48.7 13.6 -20 11 11 160.7 4.8 -20 12 1 24.5 11.8 -20 12 2 135.3 12.7 -20 12 3 172.3 9.8 -20 12 4 20.9 10.1 -20 12 5 58.3 16.1 -20 12 6 73.2 20.2 -20 12 7 84.8 8.3 -20 12 8 29.2 12.8 -20 12 9 78.7 -20 12 10 76.3 10.3 -20 13 1 197.7 9.6 -20 13 2 149.6 7.2 -20 13 3 48.4 13.7 -20 13 4 83.5 -20 13 5 94.3 6.4 -20 13 6 99.3 12.0 -20 13 7 119.9 -20 13 8 73.6 9.9 -20 13 9 94.8 6.6 -20 14 1 63.5 14.4 -20 14 2 114.4 6.8 -20 14 3 51.2 15.4 -20 14 5 44.6 13.1 -20 14 6 159.5 8.2 -20 14 7 17.7 8.9 -20 14 8 57.1 15.6 -20 15 1 84.4 -20 15 2 108.2 7.2 -20 15 3 29.9 13.4 -20 15 4 79.3 21.3 -20 15 5 25.3 11.5 -20 15 6 26.1 11.9 -20 15 7 34.4 15.1 -20 16 1 125.5 -20 16 2 65.7 12.9 -20 16 3 38.7 18.0 -20 16 4 81.4 12.3 -19 0 2 29.0 19.3 -19 0 3 71.9 24.8 -19 0 4 46.3 28.7 -19 0 5 183.1 14.1 -19 0 6 266.6 7.7 -19 0 7 209.2 5.6 -19 0 8 76.4 -19 0 9 40.4 18.1 -19 0 10 111.1 7.1 -19 0 11 127.2 6.7 -19 0 12 94.7 10.3 -19 0 13 88.2 9.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -49- -19 -19 -19 -19 -'9 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 0 14 165.1 0 15 125.5 0 16 172.3 0 17 14.1 0 18 68.9 1 1 31.0 1 I 3 28.7 I 1 4 34.7 1 1 5 97.5 1 1 6 129.6 1 7 85.5 1 8 85.3 1 9 109.3 1 10 49.3 1 II 31.9 1 12 116.3 1 13 115.4 1 14 127.0 1 I5 92.0 1 16 96.8 1 17 54.1 1 18 75.3 2 1 177.5 2 4 76.1 1 2 5 89.2 1 2 6 134.8 2 7 86.0 2 8 93.1 2 9 86.5 2 10 82.0 2 11 80.7 2 12 28.2 2 13 103.9 2 14 167.4 2 15 137.6 2 16 29.2 2 17 69.3 2 18 110.4 3 2 99.6 3 4 75.3 3 5 53.9 3 6 40.7 3 7 131.6 3 8 61.2 3 9 43.8 3 10 113.9 3 I1 67.5 3 12 23.1 3 13 103.2 3 15 71.4 3 16 64.4 -3 17 144.4 3 18 20.3 4 1 102.5 4 2 106.1 4 3 141.3 4 4 27.0 4 5 125.1 4 6 28.9 4 7 98.1 4 8 59.7 4 9 64.4 4 10 107.4 4 11 79.7 4 12 112.0 4 13 100.2 4 14 125.5 4 15 130.5 4 16 45.7 4 17 49.7 5 1 91.7 5 2 85.8 6.0 11.3 6.3 0.4 19.1 2.1 4.0 6.4 5.1 4.9 5.5 5.7 5.4 11.9 13.4 7.3 5.5 11.7 6.2 12.8 12.1 8.3 5.3 9.1 7.1 5.4 6.0 5.1 9.6 7.1 6.2 13.1 6.4 8.0 5.9 14.0 11.1 8.3 8.7 19.9 19.6 14.4 4.4 8.3 12.2 5.0 6.7 11.3 7.5 7.7 13.0 5.4 10.0 5.9 7.5 9.2 13.4 7.5 12.8 5.8 8.5 9.2 5.1 6.9 6.8 7.4 10.2 4.8 13.6 16.2 7.0 9.3 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -19 -1 5 3 144.5 5 4 105.2 1 5 5 106.5 5 6 218.2 5 7 121.5 5 8 79.7 5 9 149.1 5 10 117.5 5 il 17.3 5 12 110.1 5 13 82.4 5 14 32.9 5 15 95.6 5 16 28.7 5 17 118.5 6 1 96.2 6 2 59.1 1 6 3 26.3 1 6 4 38.8 1 6 5 150.5 6 6 68.8 1 6 7 122.4 6 8 119.3 6 9 73.9 6 10 34.2 6 11 130.5 6 12 59.4 6 13 153.1 6 14 114.6 6 15 237.7 6 16 86.3 6 17 22.2 7 1 96.2 7 2 106.0 7 3 90.1 7 4 27.4 7 5 44.0 7 6 155.1 7 7 97.7 7 8 99.8 7 9 43.5 7 10 93.9 7 11 140.3 7 12 158.4 7 13 137.1 7 14 94.3 7 15 94.5 7 16 76.0 7 17 192.4 8 1 127.2 8 2 91.5 8 3 35.6 8 4 85.4 8 5 46.8 8 6 190.1 8 7 59.8 8 8 105.3 8 9 155.9 8 10 62.2 8 11 188.9 8 12 155.6 8 13 138.6 8 14 19.9 8 15 76.6 8 16 36.0 9 1 105.2 9 2 42.3 9 3 30.6 9 4 97.6 9 5 58.2 9 6 31.8 9 7 206.4 6.1 4.3 8.0 4.5 6.1 8.8 4.4 5.5 8.7 6.5 7.7 13.0 9.0 12.3 7.8 6.1 1.0 2.3 2.9 6.5 0.3 5.6 6.7 7.1 12.8 6.7 9.5 6.3 5.9 4.7 5.8 10.6 6.0 5.8 6.8 11.5 14.8 6.2 6.7 8.5 13.3 7.5 4.7 6.3 5.3 7.2 8.2 6.3 4.4 5.5 8.7 13.2 6.9 12.4 4.7 9.8 6.1 4.4 12.3 4.3 4.5 5.0 9.8 10.5 11.4 9.5 14.2 13.3 8.3 12.4 12.2 5.8 -19 9 8 86.4 9.4 -19 9 9 124.7 6.3 -19 9 10 97.6 6.7 -19 9 11 81.7 8.1 -19 9 12 105.2 5.4 -19 9 13 129.1 5.7 -19 9 14 110.9 13.3 -19 9 15 64.9 9.6 -19 9 16 42.9 12.0 -19 10 1 38.4 13.5 -19 10 2 34.6 16.0 -19 10 3 76.8 9.6 -19 10 4 50.0 13.3 -19 10 5 29.8 12.8 -19 10 6 110.9 6.1 -19 10 7 45.5 11.9 -19 10 8 52.4 14.0 -19 10 9 123.5 4.8 -19 10 10 118.0 5.9 -19 10 11 99.3 7.5 -19 10 12 20.1 10.1 -19 10 13 109.3 8.8 -19 10 14 148.3 4.1 -19 10 15 26.0 11.5 -19 10 16 32.1 13.8 -19 11 I 78.3 9.9 -19 11 2 167.9 8.0 -19 11 3 84.3 13.9 -19 11 4 106.3 10.6 -19 11 5 20.4 10.1 -19 11 6 73.5 9.9 -19 I 7 22.6 10.5 -19 11 8 20.1 9.7 -19 11 9 52.2 11.0 -19 11 10 82.5 6.8 -19 11 11 17.5 8.7 -19 11 12 57.5 13.9 -19 11 13 52.4 11.9 -19 11 14 100.7 5.4 -19 11 15 121.8 4.4 -19 12 1 67.4 8.7 -19 12 2 107.8 7.3 -19 12 3 103.4 6.1 -19 12 4 26.7 11.6 -19 12 5 128.4 9.5 -19 12 6 96.6 9.6 -19 12 7 78.1 11.4 -19 12 8 88.1 6.7 -19 12 9 140.2 6.9 -19 12 10 38.5 12.0 -19 12 11 31.0 11.8 -19 12 12 33.0 12.8 -19 12 13 29.1 12.6 -19 12 14 123.5 5.0 -19 12 15 23.9 11.1 -19 13 1 118.4 6.5 -19 13 2 68.9 8.4 -19 13 3 296.8 5.5 -19 13 4 112.2 12.7 -19 13 5 204.6 6.5 -19 13 6 71.1 18.2 -19 13 7 113.2 8.0 -19 13 8 182.8 4.3 -19 13 9 28.1 12.3 -19 13 10 89.9 5.5 -19 13 11 62.7 7.4 -19 13 12 50.8 11.1 -19 13 13 158.3 6.8 -19 13 14 71.4 10.1 -19 14 1 118.2 6.3 -19 14 2 123.7 7.8 -19 14 3 119.0 14.7 -19 14 4 204.1 8.9 -19 14 5 184.7 -19 14 6 143.3 5.3 -19 14 7 63.9 9.7 -19 14 8 32.9 13.7 -19 14 9 79.6 10.1 -19 14 10 81.3 7.4 -19 14 11 110.2 5.2 -19 14 12 114.0 -19 14 13 65.2 7.9 -19 15 1 141.1 7.4 -19 15 2 168.2 10.1 -19 15 3 142.7 11.6 -19 15 4 141.2 6.6 -19 15 5 161.3 -19 15 6 66.3 7.9 -19 15 7 73.0 7.8 -19 15 8 65.9 -19 15 9 57.6 9.1 -19 15 10 112.0 5.6 -19 15 11 36.8 14.3 -19 15 12 54.9 11.9 -19 16 1 56.4 15.6 -19 16 2 66.1 10.9 -19 16 3 33.6 13.3 -19 16 4 151.6 -19 16 5 87.9 -19 16 6 32.0 15.3 -19 16 7 105.9 19.9 -19 16 8 81.5 -19 16 9 164.0 -19 16 10 84.7 8.3 -19 16 11 89.3 6.7 -19 16 12 143.6 -19 17 1 122.2 -19 17 2 78.4 9.6 -19 17 3 95.8 6.6 -19 17 4 77.2 10.9 -19 17 5 41.8 15.6 -19 17 6 18.4 9.3 -19 17 7 126.7 6.6 -19 17 8 33.1 13.9 -19 17 9 26.1 12.2 -19 17 10 18.2 9.1 -19 18 1 44.8 12.5 -19 18 2 28.3 12.4 -19 18 3 132.1 13.1 -19 18 4 101.1 9.1 -19 18 5 88.5 6.9 -19 18 6 52.9 10.7 -19 18,7 18.3 -19 18 8 74.5 8.4 -19 19 1 59.9 13.8 -19 19 2 21.2 10.6 -19 19 3 77.1 10.7 -19 19 4 94.0 7.4 -19 19 5 103.3 7.2 -19 19 6 96.4 6.6 -19 19 7 58.1 13.5 -19 19 8 25.3 12.3 -19 20 2 39.8 14.6 -19 20 3 68.7 17.1 -19 20 4 38.8 16.7 -19 20 5 84.1 12.9 -18 0 1 15.3 10.9 -18 0 2 170.8 -18 0 3 79.4 8.4 -18 0 4 68.8 11.6 -18 0 5 192.2 6.3 -18 0 6 59.6 11.1 -18 0 7 148.3 5.9 -18 0 8 139.2 7.8 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 o 9 135.3 6.8 o 10 240.4 8.4 0 12 244.7 6.3 0 13 70.2 8.8 0 14 226.9 6.3 0 15 159.0 6.5 o 16 57.5 17.5 0 17 146.1 12.7 0 18 110.6 7.4 0 19 76.8 21.2 0 20 169.8 6.9 1 1 219.5 4.3 1 2 94.2 5.0 1 3 91.2 5.1 1 4 105.0 4.9 1 5 42.1 12.0 1 6 38.0 10.9 1 7 35.6 11.2 1 8 23.2 11.2 1 10 219.4 5.6 1 12 89.5 6.5 1 13 61.1 7.1 1 14 219.1 4.3 1 15 96.0 7.5 1 16 72.8 9.5 1 17 117.1 6.7 1 18 79.3 8.0 1 19 116.7 11.1 1 20 54.5 13.8 2 1 163.4 5.1 2 2 137.7 4.3 2 3 106.9 6.6 2 4 98.4 5.4 2 5 112.7 7.7 2 6 209.6 3.9 2 7 90.6 6.6 2 8 124.5 4.8 2 9 53.6 13.2 2 10 226.3 8.9 12 159.2 3.9 2 13 20.8 9.5 2 14 127.0 4.9 2 15 113.2 4.8 2 16 167.8 5.2 2 17 171.6 7.5 2 18 143.2 5.1 2 19 122.7 10.1 2 20 101.7 10.0 3 1 200.8 4.7 3 2 122.8 6.0 3 3 135.4 5.3 3 4 91.4 7.6 3 5 66.1 18.7 3 6 115.5 5.0 3 7 174.4 5.5 3 8 23.9 10.9 3 9 164.7 10.9 3 10 241.3 10.8 3 11 16.0 8.1 3 12 142.1 3.9 3 13 115.9 4.7 3 14 136.0 4.6 3 15 93.4 6.5 3 16 115.9 6.0 3 17 155.6 9.1 3 18 124.9 5.0 3 19 113.8 7.3 4 1 178.2 5.4 4 2 110.1 7.1 4 3 26.0 12.2 4 4 82.8 15.2 4 5 150.2 13.8 -18 4 7 121.2 6.3 -18 4 9 182.6 9.7 -18 4 10 188.3 8.9 -18 4 12 61.0 8.3 -18 4 13 63.9 7.1 -18 4 14 62.5 8.1 -18 4 15 167.1 4.4 -18 4 16 66.8 9.0 -18 4 17 124.9 7.0 -18 4 18 93.3 7.2 -18 4 19 100.0 6.8 -18 4 20 74.8 10.3 -18 5 1 163.0 7.0 -18 5 2 214.9 10.9 -18 5 3 69.2 18.3 -18 5 5 44.4 15.3 -18 5 6 135.4 4.4 -18 5 7 131.4 6.2 -18 5 8 26.1 12.2 -18 5 9 266.7 6.9 -18 5 10 31.8 14.4 -18 5 11 32.9 13.2 -18 5 12 64.5 8.1 -18 5 13 56.9 8.6 -18 5 14 93.5 5.2 -18 5 15 105.3 7.0 -18 5 16 143.9 4.6 -18 5 17 180.3 4.6 -18 5 18 51.2 10.8 -18 5 19 72.6 7.0 -18 5 20 57.6 14.9 -18 6 1 93.5 9.7 -18 6 2 82.5 9.7 -18 6 3 111.1 7.1 -18 6 4 20.1 10.0 -18 6 6 87.0 6.4 -18 6 8 129.4 12.0 -18 6 9 251.3 9.4 -18 6 11 99.7 7.2 -18 6 12 148.3 5.1 -18 6 13 72.0 8.1 -18 6 14 27.8 11.3 -18 6 15 129.2 5.9 -18 6 16 100.0 7.2 -18 6 17 169.4 4.8 -18 6 18 41.8 141*0 -18 6 19 46.1 11.5 -18 6 20 23.5 11.2 -18 7 1 101.2 6.5 -18 7 2 48.3 14.4 -18 7 3 144.5 6.2 -18 7 4 23.8 11.5 -18 7 5 15.2 7.7 -18 7 6 116.0 5.7 -18 7 7 100.0 9.5 -18 7 8 308.7 8.7 -18 7 9 19.5 9.8 -18 7 10 35.5 13.1 -18 7 11 205.5 3.9 -18 7 12 114.3 6.7 -18 7 13 167.7 4.5 -18 7 14 211.8 4.1 -18 7 15 132.4 4.9 -18 7 16 228.2 6.0 -18 7 17 40.3 12.5 -18 7 18 77.0 8.7 -18 7 19 112.1 5.8 -18 8 1 20.8 10.3 -18 8 2 131.5 5.0 -18 8 4 25.5 11.4 -18 8 6 38.4 15.8 -18 8 7 252.0 6.7 -18 8 8 193.3 7.5 -18 8 9 129.5 6.1 -18 8 10 245.1 4.7 -18 8 11 32.5 11.6 -18 8 12 144.1 4.8 -18 8 13 40.3 13.3 -18 8 14 127.2 6.2 -18 8 15 120.6 5.3 -18 8 16 96.7 5.8 -18 8 17 19.5 9.5 -18 8 18 52.0 15.1 -18 8 19 67.4 10.3 -18 9 1 40.0 19.0 -18 9 2 76 .2 7.7 -18 9 4 108.2 7.5 -18 9 5 309.6 15.4 -18 9 6 224.0 6.4 -18 9 7 97.1 9.8 -18 9 9 98.5 5.1 -18 9 10 244.6 4.5 -18 9 11 16.5 8.1 -18 9 12 141.7 5.1 -18 9 13 117.4 5.6 -18 9 14 19.3 9.5 -18 9 15 141.8 5.3 -18 9 16 129.8 5.8 -18 9 17 155.1 4.0 -18 9 18 52.7 12.8 -18 9 19 54.7 12.6 -18 10 1 261.5 17.5 -18 10 2 238.5 10.0 -18 10 3 301.8 15.5 -18 10 4 329.8 12.3 -18 10 5 173.9 12.8 -18 10 6 108.4 11.4 -18 10 7 51.8 11.7 -18 10 9 61.8 8.9 -18 10 10 92.7 5.1 -18 10 11 181.1 4.1 -18 10 12 183.3 4.0 -18 10 13 45.2 12.4 -18 10 14 78.2 7.6 -18 10 15 106.4 5.4 -18 10 16 20.3 9.7 -18 10 17 29.5 11.5 -18 10 18 157.9 4.8 -18 11 1 190.9 15.4 -18 11 2 295.8 8.3 -18 11 3 203.9 9.3 -18 11 4 86.4 12.4 -18 11 5 82.7 8.7 -18 11 8 45.9 14.5 -18 11 9 114.7 6.2 -18 11 10 31.9 11.2 -18 11 11 146.3 4.4 -18 11 12 83.0 7.9 -18 11 13 51.8 10.2 -18 11 14 119.1 6.8 -18 11 15 53.0 10.8 -18 11.16 95.9 8.4 -18 11 17 148.3 5.7 -18 11 18 60.7 9.0 -18 12 1 28.8 13.2 -18 12 2 23.0 11.4 -18 12 5 23.8 11.6 -18 12 6 78.5 13.1 -18 12 7 100.7 5.9 -18 12 8 81.6 7.7 -18 12 9 22.3 10.5 -18 12 10 24.6 11.1 -18 12 11 52.7 12.8 -18 12 12 83.6 8.7 -18 12 13 80.2 7.9 -18 12 14 76.3 7.8 -18 12 15 72.7 9.1 -18 12 16 87.9 6.3 -18 12 17 26.7 12.1 -18 12 18 50.4 14.5 -18 13 1 45.1 14.1 -18 13 2 57.4 9.4 -18 1 3 3 68.4 10.8 -18 13 4 104.9 5.9 -18 13 5 67.1 8.8 -18 13 6 105.7 -18 13 7 103.2 5.3 -18 13 8 170.7 4.7 -18 13 9 121.7 4.6 -18 13 10 77.7 -18 13 11 62.2 9.8 -18 13 12 63.3 10.1 -18 13 13 100.9 7.7 -18 13 14 89.5 5.6 -18 13 15 91.6 -18 13 16 136.2 4.8 -18 13 17 145.0 4.8 -18 14 1 95.5 8.7 -18 14 2 113.5 5.4 -18 14 3 112.4 5.1 -18 14 4 92.3 6.1 -18 14 5 102.9 6.1 -18 14 6 127.0 4.6 -18 14 7 171.2 3.8 -18 14 8 36.7 11.4 -18 14 9 98.1 -18 14 10 21.2 9.7 -18 14 11 65.0 7.2 -18 14 12 72.5 6.9 -18 14 13 94.5 -18 14 14 50.5 12.1 -18 14 15 119.8 6.3 -18 14 16 89.3 -18 14 17 52.4 12.5 -18 15 1 21.8 10.7 -18 15 2 96.5 7.3 -18 15 3 51.0 11.8 -18 15 4 114.3 6.1 -18 15 5 126.5 6.1 -18 15 6 91.2 -18 15 7.76.7 11.7 -18 15 8 200.0 3.9 -18 15 9 45.0 11.4 -18 15 10 95.7 5.1 -18 15 11 72.9 6.8 -18 15 12 151.9 4.2 -18 15 13 159.1 6.3 -18 15 14 89.6 6.1 -18 15 15 98.0 6.3 -18 15 16 178.2 5.4 -18 16 1 89.5 6.3 -18 16 2 265.0 6.4 -18 16 3 106.5 -18 16 4 117.3 5.9 -18 16 5 66.9 9.4 -18 16 6 67.1 14.2 -18 16 7 158.2 6.9 -18 16 8 105.8 5.9 -18 16 9 114.0 5.2 -18 16 10 187.4 -18 16 11 91.6 7.9 -18 16 12 198.6 4.3 -18 16 13 162.4 7.1 -18 16 14 73.0 6.4 -18 16 15 56.8 9.3 -18 17 1 171.5 6.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCTIGB98/02542 -18 17 2 26.2 12.0 -18 17 3 144.6 5.7 -18 17 4 91.9 9.0 -18 17 5 98.1 7.8 -18 17 6 137.8 6.6 -18 17 7 62.2 9.0 -18 17 8 109.5 5.1 -18 17 9 63.7 11.8 -18 17 10 19.2 9.3 -18 17 11 65.8 10.2 -18 17 12 67.7 8.5 -18 17 13 48.7 10.9 -18 17 14 66.5 8.0 -18 17 15 75.8 7.5 -18 18 1 26.5 12.0 -18 18 2 22.1 10.8 -18 18 3 78.1 9.4 -18 18 4 173.6 5.6 -18 18 5 92.5 6.2 -18 18 6 202.0 8.1 -18 18 7 115.4 4.6 -18 18 *8 148.6 4.8 -18 18 9 31.6 11.0 -18 18 10 54.9 12.5 -18 18 11 164.6 4.2 -18 18 12 80.2 7.9 -18 18 13 45.1 14.3 -18 18 14 178.4 5.1 -18 19 1 193.6 5.6 -18 19 2 160.9 6.7 -18 19 3 203.3 5.6 -18 19 4 148.2 7.2 -18 19 5 83.2 9.4 -18 19 6 75.2 11.3 -18 19 7 120.7 17.8 -18 19 8 153.3 4.5 -18 19 9 39.3 13.2 -18 19 10 148.8 6.0 -18 19 11 107.8 5.0 -18 19 12 112.3 6.2 -18 19 13 25.6 11.7 -18 20 1 27.4 12.4 -18 20 2 123.0 6.1 -18 20 3 124.2 7.0 -18 20 4 138.6 9.6 -18 20 5 20.1 10.0 -18 20 6 26.3 12.1 -18 20 7 155.9 13.9 -18 20 8 86.9 5.0 -18 20 9 26.9 11.2 -18 20 10 126.9 5.2 -18-20 11 154.8 5.2 -18 20 12 22.6 10.8 -18 21 1 132.0 6.5 -18 21 2 143.5 8.0 -18 21 3 165.7 5.6 -18 21 4 194.3 7.5 -18 21 5 107.9 5.4 -18 21 6 40.0 14.1 -18 21 7 132.8 5.4 -18 21 8 75.0 7.4 -18 21 9 104.3 5.5 -18 21 10 131.1 5.1 -18 22 1 20.1 10.1 -18 22 2 38.8 18.3 -18 22 3 56.8 17.0 -18 22 4 35.3 14.4 -18 22 5 97.6 11.6 -18 22 6 40.9 15.0 -18 22 7 58.1 22.6 -18 22 8 46.1 18.4 -18 22 9 74.9 9.8 -18 23 1 18.4 9.1 -18 23 2 108.3 6.0 -18 23 3 29.3 12.1 -18 23 4 97.2 6.1 -18 23 5 149.2 6.4 -18 23 6 19.0 9.4 -17 0 1 99.8 23.3 -17 0 2 71.5 9.6 -17 0 3 26.6 14.9 -17 0 4 217.4 7.1 -17 0 5 19.0 12.9 -17 0 6 88.3 8.0 -17 0 7 137.6 5.6 -17 0 8 129.7. 5.8 -17 0 9 219.0 5.6 -17 0 10 53.7 24.5 -17 0 11 76.9 9.4 -17 0 12 164.3 5.1 -17 0 13 32.1 16.4 -17 0 14 222.0 11.5 -17 0 15 245.3 6.0 -17 0 16 32.1 18.0 -17 0 17 135.6 8.6 -17 0 18 67.8 11.5 -17 0 19 54.4 15.4 -17 0 20 96.1 11.9 -17 0 21 88.4 13.9 -17 0 22 124.2 9.1 -17 1 1 96.7 6.5 -17 1 2 164.4 4.0 -17 1 3 98.8 4.5 -17 1 4 30.9 11.1 -17 1 5 47.2 11.0 -17 1 6 89.4 5.6 -17 1 7 110.4 4.5 -17 1 8 125.6 5.2 -17 1 9 233.7 4.1 -17 1 10 244.1 6.0 -17 1 11 134.5 4.2 -17 1 12 226.0 3.9 -17 1 13 87.5 5.3 -17 1 14 216.5 7.8 -17 1 15 119.1 5.4- -17 1 16 103.0 8.8 -17 1 17 99.2 5.0 -17 1 18 43.5 11.4 -17 1 20 78.1 10.0 -17 1 21 111.9 5.6 -17 1 22 146.5 5.1 -17 2 1 211.3 4.8 -17 2 2 53.4 8.8 -17 2 3 156.1 4.1 -17 2 4 147.5 5.2 -17 2 5 214.7 6.0 -17 2 6 106.5 5.1 -17 2 7 202.5 4.1 -17 2 8 69.1 9.1 -17 2 9 194.0 4.3 -17 2 10 24.1 11.8 -17 2 11 57.2 9.2 -17 2 12 20.9 9.3 -17 2 14 242.4 7.2 -17 2 15 21.6 10.4 -17 2 16 150.7 4.6 -17 2 17 227.6 4.3 -17 2 18 32.9 11.7 -17 2 19 42.6 12.6 -17 2 20 214.4 4.9 -17 2 21 98.3 6.2 -17 2 22 114.4 5.6 -17 3 1 43.0 13.8 -17 3 2 156.4 4.8 -17 33 93.2 6.3 -17 34 142.7 4.1 -17 3 5 130.4 5.6 -17 3 6 203.1 3.7 -17 3 7 95.9 5.5 -17 3 8 74.1 7.5 -17 3 9 86.6 6.8 -17 3 10 149.2 4.3 -17 3 11 136.0 3.7 -17 3 12 49.4 9.6 -17 3 13 130.7 5.8 -17 3 14 361.4 6.1 -17 3 15 89.8- 7.2 -17 3 16 70.6 8.3 -17 3 17 73.7 8.4 -17 3 18 141.7 4.6 -17 3 19 95.0 6.6 -17 3 20 117.2 8.0 -17 3 21 98.1 6.6 -17 3 22 22.3 10.5 -17 4 1 177.7 6.3 -17 4 2 206.7 4.1 -17 4 3 62.2 11.1 -17 4 4 115.8 4.5 -17 4 5 167.5 9.2 -17 4 6 110.0 4.6 -17 4 7 115.0 4.8 -17 4 8 110.5 7.8 -17 4 9 184.3 4.5 -17 4 10 172.0 3.5 -17 4 11 29.1 10.5 -17 4 12 108.2 4.4 -17 4 14 268.5 11.8 -17 4 15 59.5 11.2 -17 4 16 90.2 7.2 -17 4 17 268.7 4.5 -17 4 18 78.5 6.9 -17 4 19 76.3 7.3 -17 4 20 142.3 5.8 -17 4 21 34.3 12.6 -17 4 22 187.3 4.2 -17 5 1 253.4 6.3 -17 5 2 102.7 5.7 -17 5 3 80.7 5.7 -17 5 4 105.8 7.4 -17 5 6 98.2 5.1 -17 5 7 22.6 11.1 -17 5 8 59.0 7.9 -17 5 9 65.9 6.4 -17 5 10 77.5 5.5 -17 5 11 211.9 3.9 -17 5 12 98.3 4.6 -17 5 13 87.2 7.7 -17 5 14 163.6 6.0 -17 5 15 224.9 6.0 -17 5 16 155.0 4.2 -17 5 17 171.2 5.1 -17 5 18 150.0 4.7 -17 5 19 40.8 11.8 -17 5 20 146.5 7.1 -17 5 21 41.8 13.2 -17 5 22 20.3 9.8 -17 6 1 200.5 4.1 -17 6 2 53.4 10.4 -17 6 3 121.0 5.4 -17 6 4 23.3 11.1 -17 6 5 102.4 8.3 -17 6 6 70.9 7.7 -17 6 7 119.9 4.7 -17 6 8 50.6 9.2 -17 6 9 122.2 4.7 -17 6 10 242.9 4.9 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -'7 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 6 11 97.1 4 6 13 286.71 6 15 133.8 6 16 179.2 6 17 164.9 6 18 105.9 6 19 39.5 1 6 20 86.0 6 21 119.2 6 22 122.5 7 1 225.9 7 2 20.3 9 7 3 107.1 7 4 40.5 1' 7 5 65.3 9 7 6 95.7 4 7 7 93.2 5 7 8 113.0 7 9 163.2 7 10 176.4 7 11 36.2 1 7 13 160.8 7 14 123.9 7 15 142.4 7 16 151.7 7 17 117.8 7 18 110.5 7 19 147.3 7 20 119.4 7 21 178.1 7 22 226.9 8 1 81.5 8 2 101.1 8 3 162.4 8 4 54.4 8 5 114.8 8 6 29.1 1 8 7 110.7 8 8 70.5 8 9 83.5 8 10 206.5 8 12 203.5 8 13 113.0 8 14 163.1 8 15 117.5 8 16 232.4 8 17 79.5 8 18 82.9 8 19 141.9 8 20 94.1 8 21 113.7 9 1 65.4 1 9 2 108.1 9 3 47.31 9 4 139. 0 9 5 143. 9 9 6 20.7 9 7 46.2 9 8 218.7 9 9 162.1 9 10 99.3 9 11 33 .5 9 12 260.5 9 13 19.0 F9 14 87.8 9 15 67.2 9 16 73.3 19 17 152.8 19 18 121.1 7 9 19 141.9 7 9 20 201.1 7 9 21 33.6 1.4 11.9 5.9 5.2 2.3 1 7.4 4.6 5.7 .7 1 .0 1 .7 1 4.1 3.6 3.7 1.7 9.3 5.1 4.1 7.2 6.2 6.3 5.6 4.4 5.6 18.1 5.2 1.8 4.4 6.1 5.2 6.9 5.9 5.2 4.3 9.6 5.8 8.2 ~0.1 [2.7 4.4 9.7 9.8 5.8 4.1 13.2 6.1 8.2 10.1 7.6 4.2 6.1 5.1 4.3 12.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02 542 -52- -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 17' -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 -17 10 1 118.8 10 2 78.4 10 3 109.1 10 4 54.2 10 5 109.9 10 6 246.5 10 7 20.1 10 8 61.7 10 9 215.0 10 10 191.0 10 11 239.1 10 12 285.3 10 13 107.2 10 14 138.5 10 15 89.3 10 16 100.7 10 17 214.2 10 18 116.3 10 19 74.1 10 20 67.*2 10 21 85.8 11 1 116.9 11 2 186.3 11 3 87.4 11 4 97.1 11 5 16.1 11 6 94.7 11 7 209.7 11 8 126.3 11 9 68.6 11 10 110.8 11 11 156.6 11 12 168.0 11 13 62.5 11 14 210.1 11 15 209.2 11 16 20.1 11 17 121.0 11 18 77.9 11 19 81.4 11 20 106.9 12 1 43.4 12 2 54.7 12 3 80.6 12 4 149.9 12 5 76.6 12 6 105.7 12 7 34.5 12 8 130.8 12 9 96.6 12 10 286.1 -12 11 60.0 12 12 62.9 12 13 83.5 12 14 39.0 12 15 85.0 12 16 161.6 12 17 137.5 12 18 53.5 12 19 138.3 12 20 71.7 13 1 83.9 13 2 24.6 13 3 133.0 13 4 120.2 13 5 101.9 13 6 121.3 13 8 66.1 13 9 206.2 13 11 88.3 13 12 78.8 13 13 76.6 4.5 7.0 10.2 5.1 4.7 3.9 4.1 7.1 8.3 6.6 5.6 6.1 6. 1 4.3 5.2 14.2 9.9 6.3 4.8 4.6 5.2 5.6 8.0 6.1 4.0 4.4 7.5 8.1 11.6 4.4 8.0 4.2 4.0 9.8 5.3 6-.'2 7.7 6.1 14.1 11.7 5.9 4.6 7.5 6.3 11.3 4.5 10.4 9.7 9.1 7.3 6.1 10.2 7.0 4.6 5.2 9.9 4.6 13.1 8.4 11.4 9.8 5.2 5.4 4.5 13.1 7.7 5.7 6.7 6.6 -17 13 14 75.5 8.4 -17 13 I5 138.8 4.1 -17 13 16 141.9 4.8 -17 13 17 131.2 4.7 -17 13 18 142.1 4.9 -17 13 19 214.8 4.4 -17 13 20 162.3 5.5 -17 14 1 72.3 7.1 -17 14 2 148.3 5.8 -17 14 3 18.9 9.3 -17 14 6 27.7 11.6 -17 14 7 230.5 10.4 -17 14 8 191.1 8.7 -17 14 9 146.6 4.5 -17 14 10 110.7 8.0 -17 14 11 102.2 5.0 -17 14 12 76.0 7.1 -17 14 13 32.0 12.4 -17 14 14 14.6 7.4 -17 14 15 63.5 8.4 -17 14 16 84.5 7.9 -17 14 17 51.9 12.2 -17 14 18 50.0 11.9 -17 14 19 66.7 7.8 -17 15 3 119.0 7.6 -17 15 4 126.4 14.1 -17 15- 5 246.5 10.9 -17 15 6 204.6 13.7 -17 15 7 98.1 6.3 -17 15 8 58.8 14.9 -17 15 9 158.5 4.0 -17 15 10 71.1 6.1 -17 15 11 128.9 4.2 -17 15 12 45.3 12.4 -17 15 13 61.6 8.4 -17 15 14 37.1 11.7 -17 15 15 131.8 5.4 -17 15 17 151.1 4.3 -17 15 18 62.8 8.9 -17 15 19 95.0 8.9 -17 16 1 342.8 19.6 -17 16 2 330.8 13.3 -17 16 3 228.7 8.6 -17 16 4 103.3 20.8 -17 16 6 42.2 13.3 -17 16 7 69.1 6.5 -17 16 8 222.2 4.0 -17 16 9 178.4 4.2 -17 16 10 119.4 4.7 -17 16 11 137.4 4.3 -17 16 12 96.8 4.9 -17 16 13 147.4 4.5 -17 16 14 89.6 5.9 -17 16 15 137.8 5.7 -17 16 16 91.1 5.8 -17 16 17 17.8 8.7 -17 16 18 148.9 4.2 -17 17 1 117.8 5.6 -17 17 2 38.8 16.5 -17 17 3 84.2 8.4 -17 17 4 197.6 7.3 -17 17 5 126.9 4.7 -17 17 6 26.4 11.6 -17 17 7 208.8 4.1 -17 17 8 67.3 7.6 -17 17 9 29.8 11.8 -17 17 10 79.0 6.1 -17 17 11 145.6 4.1 -17 17 12 73.3 7.9 -17 17 13 132.9 5.1 -17 17 14 117.1 4.6 -17 17 -17 17 -17 17 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 18 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 19 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 20 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 21 -17 2: -17 2: -17 2.

-17 2 -17 2 -17 2 -17 2 -17 2 15 22.2 16 19.3 17 145.9 1 114.2 2 104.1 3 58.3 1 4 69.2 1 5 103.7 7 125.4 8 96.6 9 16.5 10 169.0 11 73.7 12 181.3 13 135.5 14 23.1 15 161.3 16 75.5 17 108.0 1 71.4 2 109.5 3 117.6 4 36.2 1 5 58.4 6 87.9 7 20.7 8 45.71 9 60.6 10 158.3 11 44.4 12 157.0 13 86.3 14 115.1 15 77.3 16 76.4 1 61.2 2 168.6 3 90.5 4 135.8 5 47.4 6 141.1 7 107.5 8 105.6 9 109.0 10 91.4 11 167.0 12 140.7 13 108.3 14 24.0 15 43.6 1 148.9 2 141.2 3 106.7 4 38.8 5 68.3 6 46.2 7 73.4 8 104.4 9 124.7 10 102.1 11 50.9 12 139.1 13 133.3 114 69.1 1 68.3 2 129.8 3 185.5 Z~ 4 151.3 Z 5 111.6 2 6 95.9 2 7 144.9 2 8 25.7 10.1 9.3 4.5 6.4 5.3 1.3 0.6 8.1 4.3 7.1 8.2 4.0 6.5 5.0 5.3 10.6 4.1 7.4 5.7 7.8 5.2 5.0 .4.0 9.7 6.2 9.6 10.5 7.9 5.8 11.4 6.0 5.2 5.4 8.9 7.1 7.8 4.9 6.9 5.4 10.9 9.4 5.0 9.9 5.4 6.9 3.8 5.8 4.5 10.8 13.2 5.6 6.3 7.0 13.3 9.9 14.7 7.2 5.8 4.5 4.9 9.5 4.9 4.2 8.0 11.3 4.5 5.6 8.8 9.3 5.7 6.2 10.3 -17 22 9 21.1 -17 22 10 139.1 3.9 -17 22 11 43.1 13.8 -17 22 12 52.1 9.3 -17 22 13 23.0 10.2 -17 23 I 75.0 10.2 -17 23 2 53.5 13.1 -17 23 3 145.0 8.9 -17 23 4 27.3 11.5 -17 23 5 16.9 8.6 -17 23 6 148.9 5.2 -17 23 7 84.3 10.4 -17 23 8 152.1 4.4 -17 23 9 51.7 10.8 -17 23 10 .19.4 9.7 -17 23 11 96.5 5.1 -17 23 12 93.9 6.6 -17 24 1 49.2 13.5 -17 24 2 20.2 9.7 -17 24 3 49.1 12.8 -17 24 4 56.9 19.4 -17 24 5 133.7 -17 24 6 124.6 10.1 -17 24 7 98.8 5.2 -17 24 8 35.6 11.6 -17 24 9 16.9 8.2 -17 24 10 50.3 10.8 -17 25 1 88.4 -17 25 2 27.5 12.5 -17 25 3 31.4 12.5 -17 25 4 111.9 8.2 -17 25 5 123.2 -17 25 6 37.6 10.6 -17 25 7 22.7 11.0 -17 25 8 196.2 4.6 -1.7 26 1 37.8 13.8 -17 26 2 70.1 -17 26 3 52.0 13.3 -17 26 4 41.7 17.4 -17 26 5 64.4 21.9 -16 0 1 141.1 6.4 -16 0 2 164.8 11.2 -16 0 3 97.2 7.7 -16 0 4 182.0 5.3 -16 0 5 379.1 9.3 -16 0 6 134.4 5.9 -16 0 7 257.3 5.9 -16 0 8 35.9 15.2 -16 0 9 426.9 8.2 -16 0 11 15.3 11.0 -16 0 12 192.7 7.2 -16 0 13 90.3 8.6 -16 0 14 25.3 15.5 -16 0 I5 39.4 16.2 -16 0 16 24.9 15.7 -16 0 17 352.9 8.8 -16 0 18 154.7 6.3 -16 0 19 28.9 16.8 -16 0 20 121.7 6.4 -16 0 21 235.8 6.2 -16 0 22 98.7 7.9 -16 0 23 92.3 12.5 -16 0 24 11.2 8.4 -16 1 1 178.4 3.9 -16 1 2 152.3 6.8 -16 1 3 123.9 4.9 -16 1 4 44.1 9.6 -16 1 5 106.6 4.2 -16 1 6 244.5 3.8 -16 1 7 209.9 4.4 -16 1 8 234.1 4.6 -16 1 9 260.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -53- 1 10 216.5 4.1 1 11 85.7 6.5 I 12 22.9 9.9 1 13 27.9 11.2 1 14 224.3 3.8 1 15 28.6 11.2 1 16 199.7 3.8 1 17 285.9 6.1 1 18 14.3 7.2 1 19 184.6 4.3 1 20 100.2 5.8 1 21 108.3 5.9 1 22 32.9 11.7 1 23 59.7 15.0 1 24 62.6 9.7.

2 1 186.2 3.9 2 2 57.2 15.8 2 3 104.4 4.3 2 4 110.5 4.7 2 5 212.1 4.4 2 6 252.7 3.9 2 7 90.1 5.3 2 8 42.0 9.7 2 9 181.9 3.6 2 10 35.5 12.0 2 11 40.6 10.9 2 12 66.1 7.4 2 13 87.6 6.8 2 14 221.8 4.1 2 15 155.5 3.9 2 17 296.9 6.1 2 18 132.0 4.9 2 19 129.5 5.0 2 20 273.5 4.8 2 21 129.7 5.7 2 22 130.1 5.1 2 23 90.2 7.8 2 24 159.5 4.8 3 1 100.7 8.0 3 2 138.0 8.5 3 3 197.1 3.9 3 4 31.6 11.5 3 5 167.7 3.5 3 6 105.1 4.6 3 7 238.8 4.0 3 8 112.7 3.9 3 9 109.5 6.3 3 10 75.3 7.4 3 11 116.5 4.3 3 12 81.2 6.4 3 13 165.4 4.5 -3 14 68.5 6.8 3 15 129.2 4.8 3 17 215.6 7.0 3 18 60.8 9.4 3 19 81.2 7.5 3 20 46.9 11.0 3 21 109.8 5.8 3 22 21.7 9.9 3 23 83.0 9.5 3 24 131.8 5.7 4 1 106.1 6.7 4 2 80.3 8.0 4 3 27.2 11.4 4 4 169.2 4.1 4 5 155.5 3.6 4 6 153.3 4.3 4 7 160.6 3.9 4 8 20.7 9.3 4 9 300.2 4.7 4 10 88.6 6.2 4 11 44.3 13.5 -16 4 12 104.8 4.1 -16 4 13 192.4 4.4 -16 4 14 124.6 3.5 -16 4 15 165.8 3.9 -16 4 17 171.1 9.8 -16 4 18 67.6 9.4 -16 4 19 290.4 4.6 -16 4 20 111.0 5.3 -16 4 21 212.1 4.1 -16 4 22 142.5 4.8 -16 4 23 94.0 6.6 -16 4 24 78.5 8.6 -16 5 I 205.3 4.0 -16 5 2 103.3 4.6 -16 5 3 123.5 4.3 -16 5 4 73.2 5.7 -16 5 5 167.0 3.7 -16 5 6 89.4 4.8 -16 5 7 41.3 12.2 -16 5 8 100.5 3.9 -16 5 9 47.6 13.6 -16 5 10 130.6 5.5 -16 5 11 80.6 6.7 -16 5 12 141.3 3.7 -16 5 13 142.5 6.7 -16 5 14 144.8 4.0 -16 5 15 46.5 9.5 -16 5 17 188.2 6.5 -16 5 18 46.5 11.3 -16 5 19 54.6 11.1 -16 5 20 67.5 8.4 -16 5 21 53.7 11.3 -16 5 22 120.6 5.0 -16 5 23 15.0 7.5 -16 5 24 135.9 10.9 -16- 6 1 200.0- 4.5 -16 6 2 125.4 5.2 -16 6 3 155.6 3.8 -16 6 4 99.5 7.1 -16 6 5 150.2 3.7 -16 6 6 216.5 3.8 -16 6 7 233.6 3.9 -16 6 8 139.1 3.9 -16 6 9 83.2 5.7 -16 6 10 120.3 4.1 -16 6 11 161.6 3.7 -16 6 12 71.7 5.7 -16 6 13 179.1 3.9 -16 6 14 260.8 4.4 -16 6 15 208.0 3.7 -16 6 16 84.5 13.3 -16 6 17 25.0 12.1 -16 6 18 113.5 4.9 -16 6 19 106.0 5.8 -16 6 20 25.7 11.3 -16 6 21 118.6 4.8 -16 6 22 85.6 6.1 -16 6 23 52.7 11.4 -16 6 24 92.3 6.7 -16 7 1 29.0 11.7 -16 7 2 160.1 3.8 -16 7 3 130.5 4.3 -16 7 4 83.9 8.3 -16 7 5 105.3 4.4 -16 7 6 178.8 3.6 -16 7 7 171.5 3.7 -16 7 8 67.2 8.6 -16 7 9 200.9 3.6 -16 7 10 140.2 3.5 -16 7 11 107.5 3.9 -16 7 12 16.7 8.2 -16 7 13 313.9 5.6 -16 7 14 105.2 4.2 -16 7 15 20.6 9.9 -16 7 16 187.5 6.5 -16 7 17 15.4 7.8 -16 7 18 47.6 11.0 -16 7 19 57.9 9.2 -16 7 20 171.5 5.0 -16 7 21 92.3 7.0 -16 7 22 32.7 13.0 -16 7 23 147.3 4.2 -16 8 1 112.8 5.2 -16 8 2 165.7 4.5 -16 8 3 75.4 9.9 -16 8 4 252.5 6.3 -16 8 5 100.4 4.6 -16 8 6 189.9 3.5 -16 8 7 273.0 3.9 -16 8 8 157.4 3.9 -16 8 9 180.5 3.5 -16 8 10 106.9 4.4 -16 8 11 45.6 10.0 -16 8 12 24.5 9.7 -16 8 13 23.1 10.4 -16 8 14 125.8 4.5 -16 8 IS 54.3 12.2 -16 8 16 144.3 6.8 -16 8 18 41.0 11.2 -16 8 19 119.9 5.3 -16 8 20 86.5 7.3 -16 8 21 175.3 4.6 -16 8 22 226.9 4.9 -16 8 23 117.1 5.1 -16 9 1 89.6 6.1 -16 9 2 101.5 4.7 -16 9 3 188.0 4.4 -16 9- 4 124.9 4.8 -16 9 5 17.9 8.6 -16 9 6 126.5 4.2 -16 9 7 117.3 4.3 -16 9 8 212.6 5.4 -16 9 9 148.4 3.6 -16 9 10 172.5 3.6 -16 9 11 15.6 7.6 -16 9 12 214.5 3.9 -16 9 13 245.2 4.4 -16 9 14 19.7 9.7 -16 9 15 126.7 10.0 -16 9 16 110.3 5.6 -16 9 17 63.7 8.5 -16 9 18 57.3 8.2 -16 9 19 133.5 4.4 -16 9 20 193.0 4.2 -16 9 21 184.3 5.0 -16 9 22 139.1 5.3 -16 9 23 287.1 4.7 -16 10 1 74.9 7.1 -16 10 2 164.7 4.3 -16 10 3 24.7 10.7 -16 10 4 123.6 4.7 -16 10 5 106.2 5.3 -16 10 6 89.6 6.3 -16 10 7 90.7 5.2 -16 10 8 119.4 4.9 -16 10 9 64.6 6.2 -16 10 10 155.3 3.8 -16 10 11 235.7 3.9 -16 10 12 52.9 8.1 -16 10 13 78.4 7.0 -16 10 14 34.7 14.8 -16 10 15 199.9 6.6 -16 10 16 112.2 4.9 -16 10 17 132.5 4.2 -16 10 18 115.7 5.7 -16 10 19 24.3 10.8 -16 10 20 75.1 8.3 -16 10 21 129.0 5.9 -16 10 22 212.5 -16 10 23 82.4 -16 11 1 193 .5 4.6 -16 11 2 185.5 3.7 -16 11 3 35.1 11.5 -16 11 4 172.7 -16 11 5 79.1 7.6 -16 11 6 166.0 5.3 -16 11 7 214.2 3.8 -16 11 8 168.3 -16 11 9 165.5 4.2 -16 11 10 168.3 3.6 -16 11 11 32.6 12.5 -16 11 12 25.9 10.7 -16 11 13 148.7 4.8 -16 11 14 121.8 10.9 -16 11 15 161.3 4.8 -16 11 16 25.3 11.3 -16 11 17 241.2 4.7 -16 11 18 119.2 4.7 -16 11 19 160.8 4.2 -16 11 20 193.8 4.8 -16 11 21 142.9 4.2 -16 12 1 70.4 8.2 -16 12 2 91.8 7.2 -16 12 3 352.2 5.9 -16 12 4 119.2 4.7 -16 12 5 263.3 -16 12 6 169.7 3.4 -16 12 7 150.1 3.6 -16 12 8 139.3 -16 12 9 67.7 6.9 -16 12 10 43.2 9.6 -16 12 11 96.0 4.3 -16 12 12 55.3 7.1 -16 12 13 255.4 4.7 -16 12 14 178.1 13.1 -16 12 15 32.2 11.7 -16 12 16 29.6 11.5 -16 12 17 32.0 12.3 -16 12 18 17.7 8.7 -16 12 19 121.5 -16 12 20 146.0 5.1 -16 12 21 62.6 -16 12 22 54.0 11.4 -16 13 1 122.0 4.3 -16 13 2 60.2 -16 13 3 102.4 -16 13 4 36.4 11.6 -16 13 5 99.7 -16 13 6 57.5 6.4 -16 13 7 187.1 4.1 -16 13 8 122.0 -16 13 9 151.6 4.3 -16 13 10 144.0 3.8 -16 13 11 100.6 4.4 -16 13 13 246.1 10.1 -16 13 14 170.6 4.3 -16 13 15 115.0 5.6 -16 13 16 139.5 3.7 -16 13 17 18.9 9.2 -16 13 18 70.1 7.7 -16 13 19 255.8 4.6 -16 13 20 131.9 -16 13 21 78.7 -16 13 22 22.2 10.6 -16 14 1 161.7 -16 14 2 210.6 3.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -54- -16 I -16 I -16 1 -16 1 -16 1 -16 I -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 -161 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16, -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 51.2 11.5 189.6 4.2 23.4 10.3 187.9 3.6 120.6 3.8 142.1 4.1 157.3 3.4 71.4 5.2 196.7 4.1 167.3 9.9 182.5 4.6 127.0 4.2 110.2 4.3 169.7 3.9 157.7 4.3 90.9 7.5 114.2 5.4 160.1 6.8 52.5 14.4 92.2 6.6 152.7 4.6 79.9 5.6 176.9 6.0 253.8 9.1 108.6 3.9 71.5 7.3 173.1 4.1 138.7 3.8 16.9 8.3 167.0 9.9 143.8 13.7 113.4 4.5 241.5 4.0 21.1 9.6 112.4 5.0 115.5 4.8 220.7 4.3 109.1 5.5 179.6 4.1 91.1 8.3 34.4 11.7 124.7 5.2 128.9 4.1 151.2 4.0 102.3 5.0 103.9 4.3 179.2 5.2 49.2 11.1 53.1 15.0 249.3 12.7 1 27.4 12.2 Z 173.2 4.2 3 76.8 6.4 t 187.8 4.1 5 45.8 10.5 5 144.0 4.3 7 93.3 6.0 8 24.3 10.8 9 157.7 4.5 0 28.9 11.5 228.7 4.8 59.5 8.9 123.8 4.2 147.5 5.5 104.6 5.1 i 31.6 12.1 F 197.7 3.6 1 57.7 8.1 246.7 5.9 0 108.4 6.5 1 27.5 10.7 2 73.4 6.1 -16 I -16 I -16 I -16 1 -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 I -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 1 -16 -16 -161 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 -16 117.9 5.3 93.4 5.5 94.3 7.2 175.7 4.0 130.6 5.9 32.8 11.8 118.7 5.9 60.3 13.8 113.0 4.7 76.5 7.3 67.1 6.8 47.5 11.9 21.0 10.2 137.7 9.0 121.4 8.0 19.6 9.6 55.5 8.9 52.1 10.7 216.0 4.0 75.5 6.5 117.4 4.9 147.8 4.8 115.7 4.9 88.0 6.3 37.4 13.0 62.7 8.7 79.2 19.6 164.7 12.3 250.3 11.4 315.2 10.0 145.9 8.2 46.4 9.3 30.3 12.0 115.2 5.0 I 164.6 3.9 43.5 10.1 44.9 9.3 22.7 10.0 83.9 6.0 162.8 4.9 128.5 4.2 51.9 11.2 8 75.7 7.1 101.8 13.2 181.2 8.2 52.3 15.5 120.8 6.1 240.9 4.2 141.7 12.1 27.2 10.9 18.6 8.7 32.5 9.7 0 144.8 3.7 1 86.9 5.5 2 91.7 6.2 3 69.2 7.9 4 83.5 7.5 5 136.1 4.3 6 56.7 13.2 7 119.5 4.9 8 41.3 12.7 109.6 4.3 68.3 9.3 3 44.3 11.8 t 236.8 5.2 5 153.1 5.1 5 130.0 4.5 7 32.8 11.3 8 126.2 4.1 24.5 11.1 0 85.3 7.4 1 53.8 12.7 -16 21 1 -16 21 1 -16 21 1 -16 21 1 -16 21 1 -16 21 1 -16 22 -16 22 -16 22 -16 22 -16 22 -16 22 -16 22 -16 22 -16 22 1 -16 22 1 -16 22 1 -16 22 1 -16 22 1 -16 22 1 -16 22 1 -16 22 1 -16 23 -16 23 -16 23 -16 23 -16 23 -16 23 -16 23 -16 23 -16 23 -16 23 1 -16 23 1 -16 23 -16 23 -16 23 -16 23 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 24 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 25 -16 26 -16 26 -16 26 -16 26 -16 26 -16 26 -16 26 -16 26 146.4 5.1 104.7 4.7 103.4 5.4 138.0 5.0 33.3 11.3 157.5 5.0 174.4 7.4 64.0 8.8 180.7 4.6 106.5 5.5 73.1 7.5 130.1 4.4 168.4 5.5 36.8 11.8 114.6 5.1 91.8 5.6 148.4 3.9 108.5 4.6 165.3 4.7 105.6 5.8 39.2 12.2 38.2 12.0 102.9 4.8 80.7 9.0 107.5 10.8 203.5 5.8 81.3 7.9 121.4 6.0 135.4 5.2 116.3 3.7 116.4 4.2 181.5 3.9 85.0 6.9 18.8 9.3 144.6 4.1 55.6 8.4 78.8 7.7 122.7 8.8 62.9 9.9 89.2 6.4 79.0 7.3 86.9 8.2 48.2 9.5 87.5 5.6 89.5 6.8 37.9 11.7 98.3 5.2 1 20.6 9.6 114.2 4.7 92.2 5.9 1 35.2 12.6 128.0 4.2 42.4 12.9 161.6 8.0 122.4 6.3 116.5 4.6 61.7 9.9 82.0 6.3 121.3 3.6 1 145.4 3.7 0 66.2 6.9 1 114.6 4.6 2 36.7 12.0 3 70.3 9.6 I 66.5 17.4 68.8 8.4 3 169.2 6.2 t 48.4 10.4 5 38.6 10.8 5 107.5 9.6 7 40.0 18.2 8 115.3 6.2 -16 2, -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -16 2 -15 -15 -15 4 -15 -15 I -15 I -15 -15 -15 -15 I -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 38.9 10.6 58.6 6.8 77.8 6.4 85.3 5.6 33.3 11.8 76.4 7.6 81.0 114.1 9.4 26.4 11.1 104.2 4.7 83.0 9.7 64.6 7.2 164.6 6.6 75.5 9.7 71.3 11.6 40.1 11.5 43.0 10.8 29.3 13.7 117.8 13.0 74.9 11.3 41.8 16.3 126.7 42.9 12.3 13.5 9.8 108.6 5.3 118.3 66.9 8.9 183.7 4.9 11.9 8.6 177.3 4.8 68.2 8.4 45.4 14.8 14.2 10.0 190.2 7.3 9.2 6.9 94.2 14.2 233.1 5.3 126.6 14.0 24.5 16.5 133.8 6.2 219.7 5.7 100.0 7.1 49.2 19.7 64.7 16.0 41.1 20.5 189.8 204.8 3.8 108.3 114.5 3.9 139.8 4.1 83.8 6.2 303.2 4.8 170.2 314.8 5.1 64.6 5.2 90.8 4.7 2 237.7 3.9 3 246.4 3.9 4 76.7 5.2 5 141.7 3.3 5 107.5 7 120.7 6.3 8 18.1 8.8 9 108.1 9.3 0 65.8 8.1 1 163.6 4.1 2 257.2 5.2 3 19.5 9.2 4 93.5 6.4 5 83.2 5.9 6 117.5 6.2 1 70.0 6.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 2 2 70.0 7.6 2 3 287.6 5.4 2 4 125.2 3.3 2 5 167.9 3.6 2 6 222.0 3.7 2 7 165.8 3.6 2 8 139.5 3.9 2 9 244.6 4.3 2 10 127.4 4.1 2 11 122.9 3.9 2 12 96.8 4.4 2 13 104.1 4.3 2 14 132.3 3.8 2 15 105.8 4.3 2 17 170.4 4.4 2 18 147.7 4.1 2 19 131.2 14.1 2 20 126.4 5.0 2 21 239.1 5.3 2 22 169.5 7.3 2 23 144.4 6.1 2 24 68.2 8.3 2 25 216.1 4.4 2 26 117.0 6.5 3 1 276.5 4.4 3 2 133.5 4.9 3 3 135.7 7.2 3 4 119.7 3.9 3 5 249.7 3.8 3 6 193.5 3.5 3 7 209.6 4.2 3 8 203.9 5.4 3 9 78.5 5.2 3 10 293.8 4.8 3 11 179.2 4.1 3 12 129.0 3.6 3 13 126.3 5.9 3 14 110.5 4.0 3 15 15.1 7.5 3 16 172.1 3.7 3 17 131.1 4.2 3 18 174.4 4.9 3 19 162.9 9.4 3 20 113.6 4.4 3 21 173.3 4.0 3 22 56.0 17.2 3 23 146.0 4.4 3 24 76.5 7.5 3 25 86.8 6.3 3 26 170.0 5.4 4 1 109.6 4.5 -15-4 2 312.7 6.6 4 3 141.1 4.7 4 4 151.5 4.1 4 5 28.9 11.2 4 6 99.0 4.5 4 7 161.5 3.8 4 8 67.3 7.2 4 9 111.2 3.7 4 10 148.7 3.2 4 11 194.0 3.3 4 12 59.9 6.0 4 13 98.4 4.5 15 4 14 135.5 4.1 4 15 115.0 4.2 4 16 24.5 10.3 4 17 118.1 4.3 4 18 175.6 4.6 4 19 280.6 7.1 4 20 207.4 4.0 4 21 136.4 4.4 4 22 96.8 6.9 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -I5 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 4 23 176.1 4 24 84.7 4 25 47.5 I 5 1 315.9 5 2 289.6 5 3 189.0 5 4 308.8 5 5 71.3 6 5 6 266.6 5 7 68.47 5 8 109.8 5 9211.6 5 10 46.8 5 11 151.0 5 12 63.1 5 13 49.2 5 14 218.0 5 15 110.6 5 16 55.7 5 17 181.6 5 19 224.0 5 20 109.8 5 21 152.3 5 22 41.9 5 23 101.3 5 24 62.9 5 25 115.9 6 1 108.6 6 2 218.6 6 3 152.1 6 4 41.8 1 6 5 155.0 6 6 48.1 6 7 212.3 6 8 47.0 6 9 170.6 6 10 196.3 6 11 25.6 6 12 156.4 6 13 86.0 6 14 101.1 6 15 42.0 6 16 143.5 6 17 115.6 6 18 46.8 6 19 211.8 6 20 118.4 6 21 78.9 6 22 122.8 6 23 94.9 6 24 25.4 6 25 131.0 7 1 261.3 7 2 82.9 7 3 249.3 7 4 41.4 7 5 219.7 7 6 162.5 7 7 185.6 7 8 78.4 7 9 191.3 7 10 133.5 7 11 99.2 7 12 144.2 7 13 81.7 7 14 272.5 7 15 56.6 7 16 100.4 7 17 96.9 7 18 17.3 7 19 117.5 7 20 28.1 5.4 6.4 5.4 5.0 5.7 4.5 6.2 .2 4.2 6.3 3.6 8.8 3.5 5.4 7.8 5.1 3.6 8.6 3.7 7.8 4.2 4.1F 13.5 8.1 8.9 6.6 4.2 4.7 4.8 1.2 3.7 8.8 3.8 7.5 3.5 3.5 10.5 3.6 5.6 3.9 11.9 3.9 3.8 14.8 5.8 4.2 8.0 5.7 9.9 11.5 5.3 5.0 6.6 4.4 15.4 4.2 3.8 3.9 4.6 7.0 3.7 6.4 3.4 5.3 4.3 7.1 4.9 5.0 8.7 7.1 11.1 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -1I 7 21 116.9 7 22 47.5 12 7 23 173.3 7 24 79.6 7 7 25 78 .7 8 8 1 187.6 5 8 2 78.1 6.

8 3 168.1 5 8 4 154.1 5 8 5 52.4 6.

8 6 126.7 3 8 7 144.6 3 8 8 103.8 3 8 9 36.0 12 8 10 95.8 4 8 11 104.1 8 12 20.7 9 8 13 49.8 1 8 14 77.0 5 8 15 96.3 5 8 16 73.4 5 8 17 120.6 8 18 226.2 8 19 146.4 8 20 49.8 SJ 8 21 212.6 8 22 133.4 8 23 116.2 8 24 70.7 1 8 25 113.5 9 1 222.3 9 2 181.1 9 3 171.2 9 4285.1 9 5 72.7 6 9 6 141.7 9 7 155.1 9 8 96.8 3 9 9 183.5 9 10 333.6 9 11 127.9 9 12 128.7 9 13 20.9 9 14 164.7 9 15 50.0 1 9 16 94.4 9 17 74.5 9 18 217.9 9 19 131.7 9 20 123.2 9 21 135.0 9 22 40.51 9 23 188.5 9 24 56.21 9 25 48.5 10 1 241.6 10 2 201.9 10 3 280.4 10 4 181.3 10 5 79.3 10 6 33.8 10 7 23.7 10 8 214.7 10 9 88.4 10 10 74.1 10 11 37.9 10 12 251.6 10 13 238.4 10 14 111.2 10 15 50.4 10 16 317.0 510 19 60.2 1.7 5.5 .4 .7 1 3 6 .4 2 7 .3 .7 1 .3 4.7 1.0 .4 K 1 4.5 7.1 4.4 4.0 5.0 8.8 0.2 5.8 1.4 3.8 t.3 5.2 .8 3.8 3.8 .7 4.1 4.8 3.2 3.6 9.7 3.6 1.2 5.3 7.2 10.5 6.0 5.1 5.2 14.7 4.3 10.8 10.6 6.0 3.8 6.2 4.5 6.2 10.4 9.7 3.6 4.5 5.0 13.6 3.9 3.8 4.4 7.9 4.9 8.2 -15 10 20 112.6 4.7 -15 10 21 157.2 4.3 -15 10 22 115.3 -15 10 23 117.7 4.7 -15 10 24 69.2 7.3 -15 11 I 87.3 4,7 -15 11 2 107.5 -15 11 3 15.4 7.6 -15 11 4 194.7 3.9 -15 11 5 36.7 10.9 -15 11 6 162.2 3.4 -15 11 7 131.0 3.8 -15 11 8 70.9 -15 11 9 101.7 3.8 -15 11 10 223.9 3.7 -15 11 11 49.5 -15 11 12 152.4 -15 11 13 35.2 10.3 -15 11 14 72.4 5.3 -I5 11 15 66.7 5.4 -15 11 16 133.0 4.1 -15 11 17 311.0 -15 11 18 181.4 4.1 -15 11 19 88.9 6.6 -15 11 20 83.6 6.7 -15 11 21 217.3 4.9 -15 11 22 117.6 4.6 -15 11 23 79.0 6.6 -15 11 24 89.5 7.4 -15 12 1 136.9 -15 12 2 145.5 4.4 -15 12 3 12.4 6.3 -15 12 4 166.2 3.8 -15 12 5 148.4 3.9 -15 12 6 337.4 4.9 -15 12 7 119.0 4.4 -15 12 8 136.7 3.3 -15 12 9 324.0 4.7 -15 12 10 49.5 9.2 -15 12 11 116.2 4.3 -15 12 12 75.9 -15 12 13 165.8 4.4 -15 12 14 176.0 3.7 -15 12 15 147.8 3.7 -15 12 16 50.5 19.2 -15 12 17 69.0 7.4 -15 12 18 78.5 6.9 -15 12 19 118.9 4.1 -15 12 20 77.5 7.3 -15 12 21 214.4 4.1 -15 12 22 125.6 5.2 -15 12 23 60.5 10.9 -15 12 24 35.5 12.6 -15 13 1 77.9 6.6 -15 13 2 58.6 6.3 -15 13 3 255.9 -15 13 4 27.4 10.8 -15 13 5 82.2 4.3 -15 13 6 127.2 4.1 -15 13 7 146.9 3.2 -15 13 8 160.1 3.3 -15 13 9 145.5 3.9 -15 13 10 165.4 -15 13 11 12.5 6.3 -15 13 12 92.5 4.6 -I5 13 13 196.2 4.1 -15 13 14 19.5 -1-5 13 15 174.3 3.8 -15 13 16 196.5 7.4 -15 13 17 55.4 8.2 -15 13 18 78.5 -15 13 19 139.6 4.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 1 1

I

1

I

I

1

I

1 1 1 -151 20 56.3, 11.8 21 86.4 6.8 22 164.3 4.6 I 109.8 5.2 2 108.6 4.1 3 152.9 3.9 4 197.8 4.5 5 54.4 10.9 6 86.4 4.3 7 136.5 3.9 8 184.3 3.5 9 198.6 3.5 10 160.6 3.3 !1 134.9 3.7 12 64.4 6.4 13 128.4 3.6 14 91.5 5.0 15 215.7 6.0 16 19.0 9.3 17 77.4 6.2 18 130.7 4.0 19 181.9 4.3 20 109.9 5.1 21 16.8 8.5 22 74.7 7.9 23 33.1 13.2 1 17.6 8.5 2 141.3 4.2 3 57.1 6.8 4 181.3 5.0 5 86.7 6.2 6 154.5 3.2 7 149.0 3.5 8 263.7 4.3 9 90.7 4.3 10 69.4 6.6 11 85.4 5.4 12 91.0 4.7 13 20.2 9.2 14 54.6 8.8 15 134.1 10.1 16 118.5 5.4 17 191.9 3.8 18 402.0 6.3 19 118.9 4.5 20 53.3 12.8 21 199.6 4.7 22 47.5 11.5 23 71.5 9.4 1 50.1 10.6 2 85.2 5.5 3 79.0 6.3 4 84.6 4.9 5 47.8 7.1 6 150.7 3.4 7 23.9 10.0 8 15.9 7.6 9 102.8 4.3 10 89.3 5.5 11 222.5 3.8 12 100.2 4.2 14 349.7 8.7 15 274.9 4.5 16 69.9 6.8 17 113.3 5.5 18 209.8 4.0 19 126.1 4.0 20 119.9 5.2 5 21 107.1 6.1 i 22 150.0 4.3 F 1 121.5 4.1 7 2 100.5 5.3 -15 I -15 1 -15 1 -15 1 -15 1 -15 i -15 1 -15 1 -15 1 -15 1 -15 1 -15 I -15 1 -15 i -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 1 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15- -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 116.6 4.6 142.6 3.9 153.5 5.6 91.9 5.6 102.5 5.5 98.9 5.0 140.5 3.6 143.6 3.5 43.9 9.0 234.2 9.4 141.9 4.6 113.6 4.0 205.4 4.0 122.6 4.4 184.7 4.1 345.5 4.8 228.5 4.2 81.7 6.2 117.7 7.3 47.7 10.3 151.4 5.8 214.7 4.5 30.0 11.4 233.5 5.7 134.5 3.3 126.5 3.6 64.8 7.7 43.6 8.6 184.2 3.6 33.3 12.2 204.9 6.9 16.1 7.9 37.2 10.5 93.6 5.3 88.8 6.0 77.8 6.1 8 181.4 4.1 37.7 11.7 21.6 10.6 114.2 5.0 121.7 3.8 23.4 10.0 167.7 4.3 122.1 4.6 148.9 3.4 164.3 3.7 49.6 7.4 86.6 4.2 120.1 3.9 D 122.5 4.3 1 257-8 6.5 2 27.0 10.4 3 33.9 10.7 4 195.4 3.6 5 88.2 6.6 6 102.7 5.8 7 141.5 4.7 8 143.8 7.0 9 32.7 11.2 0 101.5 6.7 1 128.0 10.9 2 51.1 9.5 3 130.1 5.2 4 94.0 5.6 5 82.9 7.2 5 77.3 5.0 7 128.8 3.8 8 107.2 6.8 9 225.6 12.3 0 104.8 9.0 1 115.1 4.3 .2 118.5 4.2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 -15 2 -15 2 -15 2 -15 2 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 220.5 4.6 138.2 4.5 57.3 10.4 54.8 8.0 119.6 6.5 33.6 12.2 168.6 4.3 38.6 12.2 66.5 6.0 148.8 4.0 15.1 7.6 16.3 8.3 149.5 7.7 186.8 10.0 176.9 4.1 67.8 6.9 170.0 3.6 20.5 9.4 73.8 6.6 229.4 3.9 154.8 5.2 13.7 6.9 174.6 4.0 93.7 6.8 135.0 14.4 72.4 14.0 168.8 14.2 214.7 11.1 281.7 8.4 89.8 9.9 78.5 6.0 12.8 6.5 87.0 5.0 136.8 5.7 79.4 5.4 43.7 10.3 195.2 3.9 255.9 4.7 168.6 3.7 191.9 4.2 210.4 4.0 45.9 13.6 221.6 5.9 53.5 15.5 165.0 3.7 36.2 14.3 94.4 4.6 170.7 3.6 30.6 10.7 212.2 4.5 1 61.8 7.0 2 162.0 3.6 3 83.1 5.3 4 82.8 5.1 5 126.1 4.1 5 278.0 4.9 7 259.7 4.5 8 105.8 9.7 97.1 8.1 133.5 4.4 90.3 6.7 4 15.9 7.6 24.8 12.2 6 98.9 4.5 7 80.7 5.5 1 159.8 3.6 84.0 5.0 0 43.8 9.7 1 110.3 4.1 2 134.6 3.8 3 89.3 5.1 4 118.4 4.5 -15 2, -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 2 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 -15 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 ,5 ,5 .6 :6 -6 .6 6 6 6 16 26 16 16 26 26 26 27 27 -7 27 27 27 27 27 27 27 27 27 27 28 28 28 28 28 28 28 28 2' 2 2 2 2 2 2 2 2 2 2, 2, 2 3 3 3 3 3 15 16 17 1 2 3 4 5 6 7 8 9 I0

II

12 13 14 15 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 1 1: 1 1 2 3 14 15 6 6 87 8 8 9 8 1( 91 9 9 9 94 9 9 9 9 9 1 0 0 0 0 0 79.2 77.9 15.2 113.4 19.3 9 136.5 103.3 83.6 5 172.1 106.1 179.7 102.0 115.0 94.4 82.1 98.8 59.1 77.4 76.7 78.9 75.2 96.7 97.7 139.9 109.3 86.3 108.9 74.6 23.0 50.3 78.3 84.8 65.2 60.5 64.0 1 83.4 188.8 160.7 72.6 93.6 161.4 142.9 95.4 1 57.2 2 168.3 3 88.3 14.4 61.7 148.4 30.2 60.1 69.4 62.8 74.0 127.4 0 102.0 1 65.5 1 20.4 2 47.2 3 184.1 t 105.7 5 61.1 6 57.4 7 46.7 8 48.9 9 114.4 0 60.8 1 100.2 2 114.0 3 138.4 4 80.7 5 32.3 7.7 5.8 '.2 5.3 9.1 .0 4.7 6.1 4.1 4.3 4.3 5.6 5.8 8.4 5.1 7.3 7.3 6.1 4.7 7.3 4.1 7.3 10.0 11.4 7.4 8.2 3.4 6.6 7.3 6.6 4.3 5.1 3.8 4.1 7.2 4.3 7.4 7.2 16.5 4.1 13.0 9.3 6.1 19.4 5.3 4.1 4.4 9.6 14.3 5.9 3.8 15.8 10.2 9.6 4.6 7.9 4.8 5.7 4.6 6.9 10.3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -57- 30 6 18.4 9.2 30 7 27.9 13.0 -14 0 1 108.9 6.1 -14 0 2 368.5 7.4 -14 0 3 246.8 5.6 -14 0 4 254.3 6.1 -14 0 5 94.5 6.3 -14 0 6 90.3 17.1 -14 0 7 111.9 12.0 -14 0 8 15.8 10.9 -14 0 9 55.0 16.7 -14 0 10 234.5 7.5 -14 0 11 308.3 6.1 -14 0 12 157.3 4.8 -14 0 13 345.6 7.4 -14 0 14 188.0 5.1 -14 0 15 135.5 4.9 -14 0 16 8.9 6.7 -14 0 17 93.4 5.9 -14 0 18 125.2 4.8 -14 0 19 42.9 14.7 -14 0 20 52.0 16.6 -14 0 21 114.6 14.7 -14 0-22 11.7 8.6 -14 0 23 162.3 6.0 -14 0 24 247.4 6.2 -14 0 25 162.8 10.0 -14 0 26 46.9 18.4 -14 0 27 154.6 5.8 -14 1 1 92.2 4.5 -14 1 2 109.9 5.3 -14 1 3 173.9 3.9 -14 1 4 219.2 4.0 -14 1 5 193.3 3.5 -14 1 6 383.9 5.9 -14 1 7 211.2 4.6 -14 1 8 78.4 4.8 -14 1 9 186.2 3.5 -14 1 10 118.6 3.8 -14 1 11 140.9 3.7 -14 1 12 289.0 4.1 -14 1 13 403.8 6.2 -14 1 14 85.0 4.8 -14 1 15 172.1 3.9 -14 1 16 257.2 4.2 -14 1 17 234.6 3.9 -14 1 18 193.3 3.6 -14 1 19 177.9 5.6 -14 1 20 210.4 3.8 -14 1 21 196.4 8.4 -14 1 22 1.80.0 4.3 -14-1 23 160.0 4.0 -14 1 24 148.2 4.8 -14 1 25 169.8 4.5 -14 1 26 162.7 4.5 -14 1 27 106.6 5.0 -14 2 1 39.0 10.6 -14 2 2 137.7 4.7 -14 2 3 191.9 4.4 -14 2 4 274.0 4.8 -14 2 5 235.5 3.9 -14 2 6 137.7 3.8 -14 2 7 269.6 6.0 -14 2 8 28.6 10.3 -14 2 9 203.5 3.8 -14 2 10 430.3 7.6 -14 2 11 224.8 3.6 -14 2 12 15.6 7.7 -14 2 13 198.3 3.6 -14 2 14 143.1 3.4 -14 2 15 143.6 3.5 -14 2 16 20.5 9.6 -14 -14 -14 -14 -14 -14 -'4 -14 -14 -14 -14 -14 -14 -'4 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -'4 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 2 17 181.9 2 18 54.9 2 19 190.1 2 20 126.9 2 21 223.8 2 22 125.4 2 23 202.6 2 24 130.2 2 25 75.4 2 26 107.9 2 27 105.8 3 1 129.0 3 2 253.4 3 3 202.0 3 4 63.6 3 5 291.2 3 6 266.8 3 7 116.9 3 8 159.6 3 9 217.8 3 10 60.8 3 11 194.2 3 12 206.6 3 13 187.0 3 14 99.9 3 15 101.0 3 16 48.1 3 17 143.7 3 18 141.0 3 19 205.0 3 20 297.4 3 21 291.5 3 22 89.3 3 23 112.9 3 24 157.6 3 25 64.3 3 26 114.7 3 27 132.3 4 1 191.4 4 2 164.3 4 3 301.2 4 4 112.9 4 5 205.3 4 6 172.1 4 7 117.2 4 8 264.9 4 9 107.8 4 10 221.9 4 11 152.6 4 12 196.0 4 13 170.1 4 14 123.2 4 15 108.9 4 16 201.9 4 17 57.7 4 18 20.6 4 19 313.6 4 20 51.8 4 21 283.2 4 22 150.4 4 23 97.1 4 24 192.3 4 25 211.9 4 26 44.3 4 27 200.9 5 1 217.5 I5 2 280.5 15 3 177.3 15 4 245.4 I5 5 182.5 I5 6 186.7 I5 7 133.4 3.8 7.1 4.0 3.9 8.3 4.7 4.4 6.4 8.4 6.4 5.4 4.8 4.3 5.6 5.3 4.4 5.2 6.7 3.3 5.7 6.0 4.1 4.1 3.4 3.6 5.0 9.8 5.3 3.5 3.9 4.9 6.6 6.6 4.9 4.8 8.7 6.0 4.5 4.5 3.7 5.3 3.5 3.7 3.4 4.8 4.2 3.7 4.2 3.8 3.4 3.3 4.0 4.3 4.1 7.3 9.2 4.4 9.8 6.0 4.5 4.8 4.1 4.5 13.2 4.0 524 4.7 5.1 4.0 4.1 3.4 3.6 -14 5 8 360.1 4.9 -14 5 9 81.1 5.5 -14 5 10 248.7 4.6 -14 5 11 103.2 5.5 -14 5 12 377.9 5.7 -14 5 13 157.6 3.9 -14 5 14 126.0 3.7 -14 5 15 218.1 3.3 -14 5 16 147.4 4.0 -14 5 17 41.0 11.8 -14 5 18 42.0 10.1 -14 5 19 66.9 7.9 -14 5 20 159.9 5.1 -14 5 21 120.5 12.6 -14 5 22 111.3 4.5 -14 5 23 105.5 4.5 -14 5 24 84.5 6.0 -14 5 25 71.1 8.0 -14 5 26 109.5 6.5 -14 5 27 149.2 4.2 -14 6 1 239.0 3.9 -14 6 2 201.8 4.0 -14 6 3 51.3 13.4 -14 6 4 237.1 3.9 -14 6 5 25.0 10.4 -14 6 6 292.7 4.8 -14 6 7 178.4 3.5 -14 6 8 154.8 4.5 -14 6 9 149.2 3.3 -14 6 10 251.3 3.8 -14 6 11 38.6 9.2 -14 6 12 263.5 4.2 -14 6 13 297.3 4.5 -14 6 14 148.9 3.8 -14 6 15 56.7 7.3 -14 6 16 161.0 3.5 -14 6 17 251.5 3.7 -14 6 18 74.6 5.7 -14 6 19 218.8 3.8 -14 6 20 120.0 11.8 -14 6 21 37.3 14.6 -14 6 22 155.0 4.4 -14 6 23 53.6 8.0 -14 6 24 188.0 4.1 -14 6 25 65.6 8.3 -14 6 26 97.4 7.5 -14 6 27 19.7 9.6 -14 7 1 95.3 7.6 -14 7 2 308.0 4.5 -14 7 3 112.7 4.8 -14 7 4 117.7 5.1 -14 7 5 197.0 3.7 -14 7 6 308.3 4.3 -14 7 7 202.0 3.9 -14 7 8 194.7 3.3 -14 7 9 383.0 5.4 -14 7 10 423.9 5.5 -14 7 11 40.1 8.1 -14 7 12 250.9 4.6 -14 7 13 194.0 3.3 -14 7 14 127.4 4.5 -14 7 15 36.1 9.7 -14 7 16 139.9 3.6 -14 7 17 233.5 3.5 -14 7 18 27.4 10.7 -14 7 19 184.9 3.6 -14 7 20 185.4 7.2 -14 7 22 181.9 3.9 -14 7 23 83.2 6.7 -14 7 24 227.6 4.2 -14 7 25 180.8 3.9 -14 7 26 157.5 4.7 -14 8 1 147.1 6.1 -14 8 2 289.9 -14 8 3 250.4 -14 8 4 116.7 3.7 -14 8 5 22.1 9.6 -14 8 6 100.9 3.7 -14 8 7 33 7.3 5.1 -14 8 8 111.0 3.6 -14 8 9 167.0 3.9 -14 8 10 35.0 11.5 -14 8 11 187.6 3.3 -14 8 12 87.2 -14 8 13 120.1 6.7 -14 8 14 75.0 4.8 -14 8 I5 138.3 3.9 -14 8 16 74.8 6.1 -14 8 17 159.8 3 -14 8 18 2 13.2 -14 8 19 135.9 5.2 -14 8 20 269.3 9.3 -14 8 21 84.3 6.3 -14 8 22 99.9 4.8 -14 8 23 76.9 6.7 -14 8 24 75.4 6.9 -14 8 25 133.8 4.6 -14 8 26 88.9 6.7 -14 9 1 50.7 11.3 -14 9 2 154.2 4.4 -14 9 3 126.4 -14 9 4 63.1 7.7 -14 9 5 147.7 4.1 -14 9 6 58.9 5.8 -14 9 7 154.4 -14 9 8 149.9 3.2 -14 9 9 66.6 6.7 -14 9 10 55.7 5.6 -14 9 11 251.6 4.7 -14 9 12 333.4 4.3 -14 9 13 91.6 4.3 -14 9 14 219.8 3.7 -14 9 15 71.1 5.4 -14 9 16 116.1 3.9 -14 9 17 176.8 3.8 -14 9 18 144.7 -14 9 19 40.5 11.0 -14 9 20 230.6 10.1 -14 9 21 248.4 4.3 -14 9 22 184.0 4.2 -14 9 23 167.5 4.2 -14 9 24 171.1 5.8 -14 9 25 174.1 4.3 -14 9 26 67.6 9.2 -14 10 1 115.4 5.2 -14 10 2 298.7 -14 10 3 231.4 4.6 -14 10 4 61.6 -14 10 5 385.9 5.7 -14 10 6 14 .9 7.4 -14 10 7 110.6 -14 10 8 62 .0 6.1 -14 10 9 194.5 3.9 -14 10 10 36.5 9.3 -14 10 11 315.6 4.1 -14 10 12 241.2 -14 10 13 129.9 3.4 -14 10 14 73.7 -14 10 15 148.8 3.6 -14 10 16 82.5 5.3 -14 10 17 101.9 4.1 -14 10 18 156.0 4.8 -14 10 19 223.9 5.4 -14 10 20 112.3 5.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 14- -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14, -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 167.4 4.1 286.5 4.9 139.0 4.6 56.2 10.6 109.5 6.6 25.9 11.8 74.6 5.7 42.4 11.0 143.7 4.0 268.0 4.8 203.6 3.8 82.7 5.6 124.1 3.4 152.3 3.5 217.9 3.6 323.2 4.8 226.1 3.7 109.2 3.3 159.2 3.1 204.7 3.4 161.9 3.4 -232.7 3.8 81.7 5.1 188.4 3.7 239.9 8.7 205.7 4.1 35.9 11.0 185.2 4.2 93.9 6.0 166.4 4.5 128.5 5.2 124.9 7.6 53.9 11.7 319.2 5.7 182.4 3.5 128.0 4.5 148.9 3.6 21.2 9.3 147.5 3.9 84.2 4.3 202.7 4.1 78.3 4.9 83.7 5.0 50.7 7.7 165.5 3.3 134.8 3.9 38.8 10.2 131.6 3.5 169.0 8.6 188.7 4.9 31.6 11.3 86.6 5.8 136.8 4.5 58.7 10.7 101.8 5.5 157.8 4.3 214.0 3.5 208.2 4.4 28.5 9.5 33.0 10.8 28.5 9.3 78.0 5.2 142.8 3.6 70.7 5.6 14.0 6.9 1 299.5 5.2 37.8 9.1 157.5 3.4 1 71.8 5.7 5 189.2 3.3 5 90.9 5.4 7 298.1 4.3 -14 I -14 I -14 I -14 1 -14 I -14 I -14 1 -14 1 -14 1 -14 1 -14 1 -14 I -14 I -14 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 130.3 8.5 146.1 3.8 257.8 3.9 119.7 6.2 47.7 11.4 30.9 11.8 204.4 4.1 166.2 3.9 74.6 5.2 210.1 3.6 140.6 3.6 114.8 10.4 196.7 3.4 125.5 4.7 271.1 6.1 221.7 4.1 356.5 5.0 135.6 3.1 148.1 3.9 169.6 3.2 86.9 4.3 162.1 3.4 77.4 5.1 53.1 9.5 174.2 13.2 321.7 5.3 75.4 5.4 115.6 5.3 188.1 5.1 40.7 13.0 65.7 9.0 90.1 7.2 39.2 10.7 74.6 6.5 22.8 9.5 54.5 17.9 69.3 4.4 28.4 10.9 317.8 4.7 19.5 9.1 62.1 5.5 204.9 3.5 97.0 4.5 61.2 5.2 1 203.6 4.1 1 134.9 3.5 5 60.6 7.0 6 126.3 3.8 7 337.4 6.7 228.9 4.2 84.2 6.9 186.1 4.7 1 23.8 10.5 246.4 4.2 1 62.8 7.8 1 198.8 4.5 31.1 10.9 149.4 3.3 236.9 4.7 31.4 10.8 79.9 4.7 76.8 4.8 96.8 4.6 89.2 3.9 I 70.3 6.1 0 184.1 3.2 1 68.8 4.7 2 204.5 3.9 3 73.9 6.6 4 264.3 4.0 5 111.4 3.8 6 104.7 5.4 -14 I -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 I -14 1 -14 1 -14 I -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 1 -14 -14 1 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 39.5 11.8 166.5 3.8 124.2 5.1 165.3 4.2 179.3 3.9 25.8 11.0 46.1 13.6 75.3 10.6 228.1 4.4 133.4 3.7 61.5 7.5 282.4 4.3 214.5 4.0 176.2 3.4 207.9 3.6 134.3 4.4 169.4 3.4 184.6 3.4 205.7 3.5 113.5 3.8 23.0 9.7 189.5 4.1 234.4 8.2 125.5 4.5 15.7 7.9 160.6 3.9 252.1 4.5 176.2 6.3 128.2 4.1 72.6 7.0 231.4 4.5 69.2 5.4 240.6 3.9 159.4 3.5 250.1 4.4 242.8 4.1 107.0 4.7 198.2 4.2 103.9 3.3 91.8 4.5 196.7 3.8 109.5 5.7 109.6 3.8 154.2 3.8 295.0 9.0 57.3 7.8 51.6 8.6 1 281.9 4.4 124.2 5.5 1 141.6 3.8 207.2 4.1 119.2 8.1 1 100.3 7.0 97.6 5.5 46.6 9.6 155.4 4.0 101.2 5.1 60.1 8.4 297.2 4.6 83.8 4.8 148.6 3.4 P 20.5 9.4 0 160.2 3.3 2 27.3 10.3 3 145.7 4.8 4 198.8 9.1 5 164.9 3.9 6 208.1 4.5 7 108.7 4.5 8 128.7 4.0 9 188.0 4.9 0 122.9 5.8 -14 I -14 I -14 2 -14 2 -14 2 -14 2 -14 -14 7 -14 2 -14 2 -14 2 -14 -14 2 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 -14 99.2 4.4 48.7 15.1 118.4 5.1 25.9 10.7 15.6 7.7 208.1 4.3 135.0 3.3 67.9 6.4 112.4 3.3 44.4 8.6 224.8 4.2 78.9 5.6 203.4 270.8 10.4 156.4 102.7 4.7 144.5 33.3 11.3 116.7 5.1 177.3 74.8 7.2 84.9 25.9 11.1 100.4 4.6 180.5 4.2 91.7 123.1 4.2 88.2 6.8 55.3 5.8 177.2 3.7 191.9 3.4 101-.4 5.4 169.3 3.2 141.3 4.1 238.8 8.8 199.5 3.8 135.0 5 159.8 3.6 96.4 4.6 53.4 7.7 106.1 5.3 102.9 5.7 82.2 5.7 111.6 7.2 90.4 6.1 206.6 3.8 44.9 11.1 131.4 4.4 174.7 3.6 195.3 3.7 77.6 4.6 51.8 7.1 24.0 10.5 0 173.7 6.4 1 220.7 8.8 2 52.5 3 71.1 6.9 4 196.3 3.7 5 67.1 7.4 6 129.9 4.1 7 73.2 5.9 8 109.8 9 74.2 6.1 0 124.2 I 31.5 10.4 2 81.9 3 85.1 4.4 1 127.3 3.6 5 151.2 4.8 6 108.4 3.7 7 117.1 4.8 1 152.0 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -59- -14 23 -14 23 -14 23 -14 23 -14 23 -14 23 -14 23 -14 23 -14 23 -14 23 -14 23 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 24 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 25 -14 26 -14 26 -14 26 -14 26 -14 .26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 26 -14 27 -14 27 -14 27 -14 27 -14 27 -14 2, -14 27 -14 2 9 358.9 10 152.8 11 55.9 12 275.0 13 142.0 14 43.6 15 78.7 16 88.9 17 65.6 18 63.7 19 167.4 2 82.9 3 66.7 4 49.7 5 100.7 6 238.3 7 210.8 8 17.1 9 27.91 10 98.0 11 38.5 12 20.7 13 15.4 14 71.2 15 48.1 16 72.4 17 144.9 18 69.6 19 159.4 1 222.3 2 252.6 3 163.1 4 186.7 5 148.9 6 176.8 7 45.0 8 113.4 9 147.4 10 124.0 11 80.8 12 130.7 13 114.3 14 64.2 15 71.2 16 46.8 17 100.1 18 67.2 1 71.9 2 214.9 3 82.7 4 123.8 5 266.9 6 56.7 7 181.8 8 100.8 9 57.0 10 96.9 11 40.2 12 72.6 13 81.1 14 60.3 15 44.6 16 193.2 17 14.8 1 26.4 2 42.9 3 87.6 14 66.2 5 80.2 6 65.8 7 39.7 7 8 57.5 7.1 3.9 7.8 4.6 4.3 8.9 5.2 4.7 7.0 8.7 5.6 7.5 8.9 9.4 5.9 9.6 5.3 8.4 0.4 4.1 9.1 9.1 7.8 7.3 11.0 6.3 4.4 7.5 4.9 9.8 15.2 19.9 6.3 5.9 4.0 9.4 4.9 3.5 3.9 5.4 4.8 4.8 6.7 5.7 9.8 6.0 10.3 11.8 4.6 5.4 4.4 6.4 18.8 4.2 4.5 7.1 4.3 9.6 6.2 8.0 9.8 10.8 4.0 7.5 10.0 11.6 6.2 7.9 4.8 6.6 11.2 5.8 -14 27 9 80.4 5.1 -14 27 10 59.0 7.0 -14 27 11 84.6 5.8 -14 27 12 102.7 4.6 -14 27 13 100.0 4.9 -14 27 14 133.4 4.8 -14 27 15 76.4 6.4 -14 27 16 69.8 6.8 -14 28 I 102.5 5.7 -14 28 2 41.8 10.2 -14 28 3 141.2 7.0 -14 28 4 34.9 10.4 -14 28 5 113.8 5.3 -14 28 6 94.4 4.7 -14 28 7 40.8 13.5 -14 28 8 33.2 9.8 -14 28 9 218.0 4.0 -14 28 10 130.2 3.3 -14 28 11 84.7 4.5 -14 28 12 58.3 8.3 -14 28 13 113.9 4.6 -14 28 14 66.6 7.7 -14 29 1 135.6 6.7 -14 29 2 204.8 8.5 -14 29 3 21.7 10.1 -14 29 4 95.3 5.8 -14 29 5 103.9 5.6 -14 29 6 98.0 6.0 -14 29 7 23.9 10.1 -14 29 8 63.5 9.3 -14 29 9 13.9 6.9 -14 29 10 74.8 7.0 -14 29 11 41.7 13.5 -14 29 12 46.9 8.5 -14 29 13 58.8 7.6 -14 30 1 30.9 11.6 -14 30 2 190.1 4.6 -14 30 3 39.9 9.7 -14 30 4 109.2 7.9 -14 30 5 164.2 4.2 -14 30 6 155.4 3.7 -14 30 7 25.8 10.7 -14 30 8 74.4 7.1 -14 30 9 79.5 5.9 -14 30 10 34.8 12.3 -14 30 11 76.8 6.3 -14 31 I 133.5 4.5 -14 31 2 229.4 5.4 -14 31 3 78.6 11.4 -14 31 4 57.7 5.4- -14 31 5 29.5 13.5 -14 31 6 49.5 10.4 -14 31 7 46.1 10.8 -14 31 8 132.0 3.7 -14 31 9 23.6 10.6 -14 32 1 26.4 11.2 -14 32 2 141.5 5.0 -14 32 3 110.8 4.9 -14 32 4 138.8 5.0 -14 32 5 142.5 6.8 -14 32 6 107.9 5.0 -13 0 1 441.3 9.3 -13 0 2 181.2 9.4 -13 0 3 34.0 17.0 -13 0 4 99.8 5.2 -13 0 5 379.3 7.8 -13 0 6 38.1 16.9 -13 0 7 277.8 5.6 -13 0 8 16.3 11.2 -13 0 9 120.4 7.8 -13 0 10 76.7 6.6 -13 0 11 163.5 8.8 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -B3 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 0 12 69.6 0 13 238.6 0 14 73 .4 0 15 27.9 1 0 16 127.9 0 17 12.4 0 18 110.3 0 19 212.8 0 20 138.7 0 21 26.6 1 0 22 12.7 0 23 111.4 0 24 124.9 0 25 101.8 0 26 135.7 0 27 28.8 1 0 28 128.7 1 1 209.8 1 2 140.6 1 3 238.7 1 4 115.9 1 5 259.6 1 6 417.0 1 7 120.5 1 8 289.4 1 9 272.4 1 10 73.9 1 11 90.9 1 12 146.8 1 13 180.1 1 14 225.1 1 15 206.2 1 16 367.1 1 17 160.0 1 18 126.8 1 19 136.4 1 20 217.7 1 21 122.1 1 22 163.6 1 23 129.9 1 24 153.9 1 25 190.7 1 26 108.4 1 27 44.2 1 28 58.9 2 1 115.7 2 2 145.7 2 3 154.2 2 4 116.3 2 5 120.7 2 6 139.6 2 7 181.3 2 8 250.9 2 9 238.4 2 10 253.4 2 11 263.3 2 12 150.3 2 13 150.6 2 14 45.9 2 15 186.7 2 16 18.6 2 17 73.7 2 18 50.1 2 19 223.0 2 20 168.5 2 21 143.9 2 22 58.6 2 23 57.1 2 24 218.1 12 25 139.6 12 26 46.1 2 27 157.1 6.9 5.3 5.4 4.4 8.0 5.1 5.8 6.8 16.5 5.5 7.7 5.7 8.0 7.7 3.9 7.2 3.9 3.6 4.0 6.1 7.0 4.7 5.3 5.0 5.2 3.5 3.5 3.5 3.6 5.7 3.6 3.4 7.1 3.7 4.1 3.8 10.4 3.7 4.7 5.9 14.2 11.2 6.9 6.8 4.1 4.2 4.0 5.0 5.4 4.2 4.9 3.8 3.9 4.0 3.5 11.0 3.5 8.3 6.3 7.1 3.9 3.9 3.7 8.8 13.1 4.3 5.2 12.0 5.1 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -12 -12 -12 -12 -13 -13 -13

-I:

2 28 21,6.8 3 1 399.2 3 2 282.1 3 3 188.3 3 4 114.2 3 5 40.9 9 3 6 325.1 3 7 348.7 38 375.2 3 9 193.5 3 10 82.5 3 11 229.5 3 12 175.5 3 13 158.3 3 14 273.7 3 15 173.8 3 16 60.2 3 17 196.3 3 18 66.1 3 19 308.2 3 20 423.2 3 21 152.4 3 22 153.2 3 23 73.1 3 24 252.2 3 25 39.7 1 3 26 69.3 3 27 200.9 3 28 176.5 4 1 21.8 1 4 2 233.2 4 3 281.7 4 4 195.8 4 5 295.2 4 6 256.2 4 7 149.5 4 8 338.5 4 9 79.6 4 10 146.0 4 11 23.5 4 12 193.1 4 13 160.7 4 14 148.9 4 15 192.1 4 16 247.1 4 17 145.0 4 18 203.6 4 19 96.5 4 20 318.0 4 21 66.6 4 23 24.2 4 24 206.0 4 25 136.4 4 26 108.6 4 27 95.5 4 28 255.6 5 1 232.1 5 2 182.5 5 3 87.8 5 4 159.4 5 5 219.5 5 6 70.6 5 7 64.2 5 8 17.4 5 9 166.5 5 10 176.2 5 11 152.6 15 12 67.9 15 13 194.9 15 14 194.1 15 15 87.3 5 16 68.5 4.8 1.6 1 t.3 .6 5.2 5.9 4.2 4.1 3.2 3.8 3.2 5.6 3.4 4.9 5.6 3.7 7.4 4.3 2.2 9.2 5.3 4.4 0.1 4.6 5.1 4.9 4.6 5.1 9.9 3.6 3.9 3.6 3.6 4.8 3.6 3.6 4.6 8.9 11.1 4.2 5.9 6.9 4.8 4.6 3.8 5.8 5.7 5.3 6.2 3.4 3.7 3.6 6.8 3.3 3.4 3.8 5.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 17 97.2 4.3 18 93.1 5.7 19 162.7 3.3 20 41.2 11.5 21 327.8 4.7 22 53.4 17.6 23 139.5 5.2 24 83.1 5.9 25 159.0 4.1 26 127.5 9.1 27 98.4 7.1 28 114.6 6.2 6 1 105.9 5.9 6 2 418.2 6.7 6 3 114.8 7.0 6 4 89.0 5.7 6 5 520.5 8.7 6 6 121.8 3.7 6 7 182.2 4.0 6 8 203.8 3.4 6 9 167.0 3.4 6 10 111.9 4.3 6 11 129.2 3.7 6 12 328.6 5.0 6 13 336.7 4.7 6 14 77.3 5.0 6 15 255.4 5.0 6 16 201.3 3.7 6 17 63.5 6.3 6 18 143.5 3.7 6 19 254.0 4.2 6 20 221.8 4.5 6 21 190.8 3.6 6 22 280.4 6.9 6 23 233.2 4.5 6 24 173.1 4.7 6 25 84.6 6.7 6 26 132.7 6.2 6 27 39.1 14.1 6 28 140.8 4.6 7 1 103.3 6.2 7 2 174.5 3.9 7 3 168.3 4.7 7 4 354.7 5.3 7 5 375.8 5.1 7 6 127.6 5.4 7 7 114.6 3.8 7 8 273.0 4.0 7 9 68.0 6.7 7 10 165.8 3.3 7 11 267.3 4.2 -7 12 36.5 12.4 7 13 205.3 3.6 7 14 111.5 4.1 7 15 39.0 10.2 7 16 220.8 3.5 7 17 108.3 3.9 7 18 142.6 3.7 7 19 131.9 4.2 7 20 146.5 3.4 7 21 34.0 11.4 7 22 275.4 8.6 7 23 154.1 3.8 7 24 212.6 4.1 7 25 57.9 10.8 7 26 198.9 4.2 7 27 109.7 5.0 7 28 186.5 4.4 8 1 215.3 5.4 8 2 179.3 4.2 8 3 170.5 4.8 8 4 74.3 5.9 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 8 5 130.9 8 6 85.3 5 8 7 87.4 4 8 8 152.4 8 9 281.6 8 10 151.0 8 11 116.8 8 12 163.6 8 13 34.2 8 14 158.7 8 15 41.4 1 8 16 41.4 1 8 17 203.3 8 18 65.2 8 1.9 19.6 8 20 141.1 8 21 22.8 1 8 22 257.1 8 23 93.9 8 24 127.1 8 25 91.9 8 27 125.2 9 1 346.6 9 2 138.9 9 3 132.1 9 4 28.79 9 5 74.45 9 6277.3 9 7 124.8 9 8 208.9 9 9 198.4 9 10 182.5 9 11 211.8 9 12 57.1 9 13 280.4 9 14 191.8 9 15 224.3 9 16 44.2 9 17 182.0 9 18 202.9 9 19 152.5 9 20 162.1 9 22 116.7 9 23 151.5 9 24 110.6 9 25 68.4 9 26 189.9 9 27 256.9 10 1 107.8 10 3 93.1 10 4 124.1 10 5 133.6 10 6 100.2 10 7 238.9 10 8 51.2 10 9 100.4 10 10 191.6 10 11 214.2 10 12 221.3 10 13 80.4 10 14 156.0 10 15 248.2 10 16 134.4 10 17 302.3 10 18 70.6 10 19 44.3 10 20 296.4 10 21 258.0 10 22 125.9 10 23 153.0 10 24 230.8 10 25 156.4 1.5 1 .2 3.8 1.2 .3.2 3.6 3.2 2.1 1.0 3.6 6.8 3.7 0.1 11.1 8.1 4.8 7.1 4.5 6.2 3.5 4.8 4.5 .3 4.2 4.1 3.6 3.4 3.3 3.3 6.8 4.4 4.9 3.6 8.2 3.6 3.6 7.9 3.6 5.4 5.0 5.8 7.9 4.0 4.7 4.1 6.3 3.4 3.4 5.3 3.7 6.8 3.8 3.3 4.0 3.5 5.5 3.3 3.8 3.4 4.2 5.4 10.5 4.7 6.1 5.1 4.4 5.3 4.0 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 10 26 110.8 10 27 89.5 11 1 133.4 11 2 228.5 11 3 103.2 11 4 257.6 1 1 5 587.3 11 6 24.5 1 11 7 256.3 11 8 270.0 11 9 107.5 11 10 121.3 11 11 288.0 11 12 150.2 11 13 119.1 11 14 71.3 11 15 68.6 11 16 247.2 11 17 127.3 11 18 127.5 11 19 61.9 11 20 223.9 11 21 245.4 11 22 141.6 11 23 90.6 11 24 93.8 11 25 66.3 11 26 50.9 11 27 82.7 12 1 173.8 12 2 110.7 12 3 185.7 12 4 75.8 12 5 308.0 12 6 131.5 12 7 148.5 12 8 258.0 12 9 85.3 12 10 183.5 12 11 39.6 12 12 150.2 12 13 113.4 12 14 122.2 12 15 88.0 12 16 95.4 12 17 58.9 12 18 136.7 12 19 208.9 12 20 186.9 12 21 16.1 12 22 180.1 12 23 103.4 12 24 87.0 12 25 46.5 12 26 68.1 13 1 236.6 13 2 126.1 13 3 192.3 13 4 287.5 13 5 173.5 13 6 139.3 13 7 181.1 13 8 246.8 13 9 203.3 13 10 157.2 13 11 137.0 13 12 197.3 13 13 34.1 13 14 57.2 13 15 53.8 13 16 224.8 13 17 278.6 5.6 6.5 4.4 5.0 4.2 3.8 7.8 0.2 4.5 4.1 5.6 3.5 4.4 4.6 5.1 5.1 4.0 3.3 3.9 6.8 3.9 7.8 4.1 8.0 5.3 7.6 9.7 6.4- 6.6 4.0 3.6 6.2 4.6 3.9 3.1 4.0 4.5 3.3 9.1 4.1 3.6 3.4 4.6 5.2 5.9 3.8 4.3 4.7 8.1 3.8 4.8 5.3 12.5 7.6 3.8 3.6 4.2 4.5 3.1 3.2 3.2 3.8 3.6 3.2 3.8 3.3 10.1 6.9 6.6 4.2 4.4 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -'3 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 13 18 198.2 13 19 198.5 13 20 184.7 13 21 152.3 13 22 18.9 13 23 88.3 13 24 260.0 13 25 126.6 13 26 30.8 1 14 1 252.8 14 2 220.4 14 3 152.8 14 4 185.9 14 5 107.6 14 6 38.1 14 7 82.1 14 8 117.6 14 9 118.3 14 10 133.8 14 11 101.0 14 12 123A 14 13 82.5 14 14 63.0 14 15 258.5 14 16 172.8 14 17 112.0 14 18 170.7 14 20 218.2 14 21 17.8 14 22 74.0 14 23 181.4 14 24 143.6 14 25 84.1 14 26 239.7 15 1 137.4 15 2 297.8 15 3 194.1 15 4 210.4 15 5 64.7 15 6 134.3 15 7 172.9 15 8 145.8 15 9 98.0 15 10 137.9 15 11 211.3 15 12 104.5 15 13 67.6 15 14 38.6 15 15 138.0 15 16 139.9 15 17 77.7 15 18 15.8 15 19 312.1 15 20 174.2 15 21 165.7 15 22 27.2 15 23 167.0 15 24 186.0 15 25 115.7 16 1 108.3 16 2 271.0 16 3 115.9 16 4 21.8 16 5 41.7 16 6 51.3 16 7 252.2 16 8 134.9 16 9 73.6 16 10 23.9 116 11 170.5 116 12 43.4 116 13 67.2 4.2 7.3 3.9 6.9 4.9 1.8 3.9 4.6 3..4 3.9 3.9 '.9 .4 3.4 4.4 3.2 3.8 4.3 7.3 7.4 3.9 3.3~ 4.4 4.2 8.6 5.1 6.9 4.9 3.3 7.2 3.1 3.2 3.2 3.7 3.7 5.1 10.7 3.3 6.7 7.8 11.9 3.9 11.6 3.9 4.2 4.9 7.2 8.9 8.2 11.4 3.8 3.9 5.9 3.8 4.8 SUBSTITUTE SHEET (RULE WO 99/10379 PCT/GB98/02542 -13 1 -13 I -13 I -13 I -13 1 -13 1 -13 I -13 1 -13 1 -13 1 -13 1 -13 1 -13 1 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 136.9 3.3 262.6 4.5 177.2 3.4 273.2 4.8 121.4 6.0 134.3 3.9 257.1 4.2 71.9 7.5 267.6 4.8 85.4 6.5 104.4 6.0 159.1 4.1 161.2 3.9 177.0 3.5 192.7 4.9 191.5 3.2 159.2 3.1 125.6 3.4 108.8 3.3 106.9 3.3 201.7 3.8 247.5 3.7 120.1 3.6 215.3 3.6 26.9 10.7 236.6 3.7 93.9 4.3 199.4 4.4 203.5 6.4 183.4 4.2 127.2 4.2 261.1 4.4 73.6 6.6 143.9 4.6 42.2 12.1 119.7 5.4 90.3 4.4 82.9 5.0 100.0 3.9 175.7 5.0 304.1 5.0 169.1 3.6 161.9 3.6 59.0 7.6 139.9 3.0 132.1 3.2 245.8 3.8 143.7 3.8 21.4 9.1 59.1 6.7 167.6 3.5 151.7 3.6 207.0 8.7 172.3 4.4 90.8 6.8 1 162.2 4.0 30.2 10.9 t 134.6 4.1 1 48.3 10.9 1 77.0 7.4 241.6 3.9 17.0 8.0 64.9 6.2 170.4 4.0 131.8 2.9 216.2 4.2 200.7 3.2 48.4 6.5 238.3 3.8 0 147.2 3.0 1 80.7 4.3 2 117.6 3.7 -13 19 I -13 19 1, -13 19 1 -13 19 1 -13 19 1 -13 19 1 -13 19 1 -13 19 2 -13 19 2 -13 19 2 -13 19 2 -13 19 2 -13 20 1 -13 20 -13 20 -13 20 -13 20 -13 20 -13 20 -13 20 1 -13 20 1 -13 20 1 -13 20 1 -13 20 1 -13 20 I -13 20 1 -13 20 1 -13 20 1 -13 20 1 -13 20 1 -13 20 2 -13 20 -13 20 -13 20 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 21 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 -13 22 61.2 5.6 133.5 3.3 117.7 4.0 81.0 8.3 14.4 7.2 101.7 5.2 154.8 3.8 63.7 9.2 78.8 6.8 253.9 4.5 138.5 4.2 55.3 9.0 250.2 4.6 76.7 4.8 70.4 4.6 106.7 3.9 138.8 3.8 82.8 4.4 158.4 3.1 74.1 5.5 150.3 3.3 139.6 3.2 153.8 3.9 232.3 4.0 45.3 7.0 36.4 10.7 50.4 16.8 24.8 11.3 202.8 3.8 226.9 4.0 124.1 4.2 177.3 3.9 192.9 4.0 83.1 7.6 71.2 9.5 98.2 4.8 25.6 9.9 63.7 11.9 231.4 4.3 74.7 4.1 155.5 3.4 187.5 3.1 71.2 4.2 1 90.8 3.6 38.0 13.6 3 16.4 8.1 1 60.0 8.8 5 66.1 13.8 5 113.7 5.2 7 163.9 4.4 8 144.1 4.2 16.0 8.0 22.9 10.3 1 101.1 4.6 2 35.0 10.9 194.2 5.2 110.7 3.4 109.0 4.4 15.2 7.2 192.0 5.0 145.0 3.0 161.6 3.1 8 130.8 3.7 225.6 4.0 0 195.5 3.4 1 77.4 5.0 2 83.3 4.3 3 194.1 3.9 4 146.5 13.9 5 67.0 7.0 6 157.3 3.5 7 29.6 11.0 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 2 -13 -13 -13 2 -13 2 -13 -13 2 -13 2 -13 2 -13 -13 -13 -13 2 -13 -13 2 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 -13 216.9 4.2 110.9 4.5 109.6 5.1 44.4 11.4 123.5 5.6 124.4 4.2 90.0 8.6 20.1 9.9 210.8 4.4 174.8 3.1 100.0 4.2 144.4 3.7 189.8 3.2 176.6 3.3 199.2 7.7 174.7 4.1 126.2 5.0 115.1 4.0 150.3 4.6 70.0 6.3 68.0 7.1 152.7 4.0 175.0 4.7 102.1 4.6 252.6 6.6 152.0 3.6 104.9 5.5 67.6 5.2 112.8 4.6 148.5 3.4 102.2 3.8 123.1 3.1 55.9 6.1 110.7 4.6 208.6 6.5 186.3 3.5 159.5 3.5 41.1 9.0 223.2 4.1 143.5 3.9 104.3 4.4 48.9 10.2 41.1 11.7 59.8 9.7 25.8 9.5 107.6 4.8 81.4 5.4 120.6 3.5 96.2 5.8 64.8 7.7 25.3 9.1 38.6 9.2 288.7 8.5 0 98.9 4.7 i 86.6 3.8 2 106.4 4.3 3 152.9 3.7 4 120.5 3.9 5 63.5 6.8 6 133.1 3.9 7 79.3 5.3 8 95.3 5.5 9 21.0 9.9 0 57.2 13.1 1 117.7 7.8 5 135.5 4.1 t 111.2 8.7 5 96.3 4.9 5 302.6 8.3 7 211.7 6.1 8 156.5 4.3 23.6 9.9 -13 26 I -13 26 I -13 26 1 -13 26 1 -13 26 I -13 26 1 -13 26 1 -13 26 1 -13 26 I -13 26 1 -13 27 -13 27 -13 27 -13 27 -13 27 -13 27 -13 27 -13 27 I -13 27 1 -13 27 1 -13 27 1 -13 27 1 -13 27 1 -13 27 1 -13 27 1 -13 27 1 -13 27 1 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 28 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 29 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 -13 30 166.3 154.2 3.4 139.3 3.3 122.2 4.2 179.1 4.2 108.1 113.4 4.6 133.5 4.2 71.7 6.3 64.5 7.3 243.1 13.3 137.2 12.1 130.4 5.7 245.9 5.1 109.7 5.1 259.9 3.9 27.6 9.6 72.9 45.6 6.9 92.1 196.6 3.6 109.9 4.2 136.8 137.0 3.7 193.4 3.6 75.1 5.7 92.8 146.8 3.9 112.3 4.4 65.7 5.1 26.9 11.1 115.0 62.4 26.7 11.4 22.9 190.1 104.7 90.2 4.8 182.2 3.6 112.5 4.4 83.5 8.9 115.9 4.2 20.5 9.4 107.6 5.2 20.4 8.9 135.6 5.9 64.2 9.2 34.3 11.2 124.6 66.9 20.7 126.0 3.2 84.5 0 225.8 3.8 1 191.1 3.4 2 102.5 4.1 3 172.5 4 71.8 5.6 5 117.5 69.6 11.5 181.6 5.4 135.3 6.2 19.8 9.8 29.4 10.9 6 184.9 8.4 7 60.1 7.9 8 123.0 9 90.5 5.3 0 128.2 3.2 1 35.6 13.2 2 217.5 3.7 3 22.7 9.8 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -13 30 14 61.6 7.7 -13 31 1 253.2 5.3 -13 31 2 115.2 9.5 -13 31 3 119.9 4.7 -13 31 4 133.5 5.5 -13 31 5 144.6 3.5 -13 31 6 87.0 4.1 -13 31 7 93.7 4.7 -13 31 8 111.7 3.0 -13 31 9 132.2 3.8 -13 31 10 133.2 3.4 I 311I 79.4 5.6 -13 31 12 119.7 4.0 -1.3 31 13 85.8 5.8 -13 32 1 20.7 9.5 -13 32 2 30.1 13.4 -13 32 3 153.5 3.8 -13 32 4 197.0 5.1 -13 32 5 164.8 6.2- -13 32 6 115.5 4.0 -13 32 7 114.8 6.4 -13 32 8 186.4 4.6 -13 32 9 216.1 3.7 -13 32 10 26.7 11.2 -13 32 11 174.6 4.1 -13 33 1 56.5 8.2 -13 33 2 108.8 5.8 -13 33 3 100.5 3.9 -13 33 4 36.2 11.9 -13 33 5 114.4 4.6 -13 33 6 235.2 6.3 -13 33 7 144.5 3.9 -13 33 8 75.3. 8.0 -13 34 1 75.9 7.1 -13 34 2 38.2 10.0 -13- 34. 3 34.6 15.6 -13 34 4 80.2 15.4 -13 34 5 80.5 9.4 -12 0 1 120.7 15.9 -12 0 2 396.2 10.2 -12 0 3 89.1 9.1 -12 0 4 110.6 6.9 -12 0 5 174.3 8.0 -12 0 6 203.4 5.4 -12 0 7 352.0 7.3 -12 0 8 82.6 8.7 -12 0 9 417.2 9.1 -12 0 10 158.5 4.9 -12 0 11 98.3 8.1 -12 0 12 262.2 7.7 -12 0 13 341.1 6.4 -12-0 14 416.2 11.2 -12 0 15 207.8 4.9 -12 0 16 147.5 4.4 -12 0 17 120.1 4.8 -12 0 18 114.1 4.9 -12 0 19 154.3 4.4 -12 0 20 41.8 20.1 -12 0 21 88.2 11.0 -12 0 22 91.0 5.7 -12 0 23 10.2 7.6 -12 0 24 190.4 12.7 -12 0 25 70.5 8.9 '12 0 26 73.4 11.0 -12 0 27 155.2 9.8 -12 0 28 23.3 14.4 -12 0 29 142.2 12.0 -12 1 1 204.5 6.7 -12 1 2 448.5 7.3 -12 1 3 307.2 4.7 -12 1 4 548.6 7.0 -12 1 5 320.9 5.0 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 1 6 600.5 1 7 45.5 1 1 8 193.1 1 9 155.5 1 10 79.8 1 11 75.2 1 12 255.8 1 13 80.8 1 14 121.5 1 15 18.4 1 16 78.8 1 17 229.5 1 18 166.6 1 19 245.7 1 20 128.2 1 21 100.7 1 22 191.2 1 23 106.4 1 24 204.4 1 25 154.5 1 26 158.3 1 27 77.5 1 28 141.4 1 29 22.7 2 1 431.3 2 2 114.4 2 3 92.2 2 4 353.7 2 5 262.0 2 6 75.9 1 2 7 406.7 2 8 225.7 2 9 220.3 2 10 120.2 2 11 76.2 2 12 188.0 2 13 98.0 2 14 44.1 2 15 523.8 2 16 22.5 2 17 100.4 2 18 63.1 2 19 154.8 2 20 115.2 2 21 90.6 2 22 176.6 2 23 15.7 2 24 209.2 2 25 166.2 2 26 99.7 2 27 188.1 2 28 52.8 2 29 242.7 3 1 225.4 3 2 376.9 3 3 385.9 3 4 231.2 3 5 146.7 3 6 18.7 3 7 111.0 3 8 155.8 3 9 147.6 3 10 314.5 3 11 276.8 3 12 214.9 3 13 126.9 3 14 225.3 3 15 215.2 3 16 235.6 3 17 170.2 3 18 164.9 3 19 42.1 8.8 0.2 3.5 6.0 5.5 4.7 4.3 4.9 5.7 8.8 4.8 3.6 3.2 4.0 4.0 7.0 3.6 5.2 7.6 4.7 4.2 12.4 4.0 10.9 8.1 8.6 6.6 4.6 4.1 0.1 7.7 3.9 4.0 6.6 4.4 3.9 4.5 8.8 7.4 9.5 7.4 5.1 3.8 4.6- 6.1 3.6 7.8 8.0 4.8 10.9 4.8 10.7 4.7 8.6 5.8 5.5 3.9 3.7 9.0 7.1 3.5 3.6 4.5 4.5 3.5 3.8 3.7 3.7 5.5 3.4 3.4 8.7 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 3 20 95.5 3 21 19.9 3 22 188.6 3 23 146.1 3 24 292.0 3 25 298.4 3 26 47.4 3 27 127.1 3 28 207.9 3 29 97.5 4 1 170.3 4 2 196.8 4 3 310.0 4 4 660.3 4 5 19.3 4 6 193.2 4 7 387.6 4 8 247.6 4 9 239.1 4 10 50.3 4 11 108.0 4 12 348.2 4 13 200.3 4 14 167.4 4 15 200.1 4 16 160~3 4 17 151.3 4 18 239.9 4 19 135.9 4 20 267.2 4 21 156.6 4 22 77.4 4 23 99.2 4 24 269.5 4 25 180.0 4 26 224.7 4 27 116.9 4 28 182.5 4 29 75.8 5 1 159.3 5 2 401.3 5 3 167.7 5 4 311.8 5 5 491.4 5 6 244.1 5 7 160.3 5 8 24.6 5 9 339.8 5 10 200.3 5 11 116.2 5 13 114.4 5 14 127.4 5 15 169.8 5 16 153.7 5 17 65.1 5 18 95.3 5 19 182.7 5 20 208.2 5 21 173.5 5 22 230.3 5 23 203.4 5 24 140.8 5 25 110.1 5 26 118.4 5 27 102.2 5 28 34.5 5 29 84.5 6 1 75.0 6 2 210.7 6 3 116.5 6 4 273.3 6 5 88.4 5.2 9.6 3.7 3.8 9.8 4.9 12.5 5.5 4.1 8.0 4.3 4.4 5.0 9.8 9.5 3.8 5.1 5.9 3.9 6.7 4.0 5.6 3.5 3.3 3.6 3.3 3.2 3.8 3.3 4.1 3.8 6.7 4.9 10.7 4.1 4.0 6.0 5.7 8.8 4.9 6.1 3.6 5.3 7.5 4.4 5.3 11.4 6.1 3.7 3.7 4.2 4.0 3.7 4.0 6.4 4.2 3.3 3.8 3.6 3.7 4.1 12.6 5.3 5.3 6.4 12.8 8.0 11.6 4.7 3.7 4.6 5.1 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 6 6 232.2 6 7 147.1 6 8 202.6 6 9 379.7 6 10 51.8 6 11 327.7 6 12 216.3 6 13 170.2 6 14 89 .6 6 15 130.4 6 16 132.2 6 17 67.7 6 18 199.4 6 19 174.6 6 20 264.2 6 21 21.5 6 22 207.0 6 23 386.8 6 24 120.4 6 25 134.3 6 26 330.3 6 27 88.0 6 28 57.3 6 29 59.01 7 1 452.5 7 2 229.2 7 3 192.4 7 4 151.9 7 5 248.6 7 6 146.8 7 7 240.4 7 8 205.4 7 9 216.5 7 10 158.0 7 11 20.7 7 12 291.5 7 13 275.5 7 14 168.9 7 15 207.6 7 16 157.3 7 17 109.4 7 18 201.7 7 19 93.6 7 20 128.8 7 21 195.1 7 22 41.0 7 24 69.5 7 25* 20.1 7 26 71.2 7 27 224.2 7 28 138.7 7 29 160.5 8 1 302.6 8 2 258.5 8 3 142.9 8 4 158.7 8 5 457.2 8 6 184.5 8 7 164.9 8 8 356.7 8 9 103.0 8 10 393.2 8 11 171.4 8 12 269.1 8 13 131.9 8 14 257.0 8 15 152.0 8 16 335.7 8 17 54.9 8 18 166.1 8 19 99.9 8 20 243.1 3.6 5.7 8.3 4.6 3.6 6.3 3.6 3.6 6.2 3.4 3.2 4.3 9.8 3.7 6.8 4.7 5.2 6.1 13.0 14.2 7.1 4.8 3.9 3.6 4.4 3.7 4.3 3.6 3.6 3.6 9.2 4.8 4.6 3.3 3.7 4.9 3.6 3.

4.4 3.4 11.4 8.6 6.9 4.3 4.8 4.8 4.3 3.4 3.8 6.6 3.6 4.6 6.1 4.9 3.6 3.9 3.3 5.4 7.4 3.3 3.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/G B98/02542 -63- -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12.

-12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 136.1 3.4 145.9 3.8 150.8 9.8 230.4 4.1 55.8 10.5 138.5 4.5 1.7.9 9.0 107.5 6.4 85.2 8.4 325.9 5.6 404.4 7.4 86.3 7.7 366.5 5.0 184.7 3.9 219.8 3.9 134.8 3.4 106.7 3.6 191.4 3.8 259.5 3.8 227.9 3.7 147.3 3.6 119.9 4.0 113.7 3.7 166.0 3.9 31.0 9.5 33.5 10.7 316.8 4.7 166.5 3.4 260.0 3.9 130.2 3.4 174.6 3.6 242.6 7.8 154.6 3.9 251.9 4.4 153.6 4.2 311.9 5.0 169.3 5.1 181.5 4.5 62.2 8.4 323.0 7.8 60.8 6.7 156.0 3.4 72.8 5.8 82.3 6.1 322.3 4.9 117.8 3.6 0 199.6 3.4 1 147.3 3.5 2 106.2 3.6 3 109.1 4.1 4 61.7 6.4 5 179.3 3.3 6 113.6 3.6 7 119.6 6.0 8 180.0 3.3 9 92.5 5.2 0 119.9 4.2 1 229.0 3.8 2 57.2 10.7 3 26.0 12.1 4 149.4 3.9 5 76.7 5.8 6 139.5 4.8 7 119.5 6.5 8 195.7 4.4 1 560.2 10.1 2 103.6 8.3 3 416.2 8.2 4 109.3 3.8 5 340.5 5.8 5 241.5 4.6 7 53.1 6.4 -12 1 -12 1 -12 1 -12 I -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 I -12 1 -12 1 -12 1 -12 I -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 -12 -12 1 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 8 147.1 3.4 9 323.6 4.8 10 177.4 3.8 11 364.1 5.1 12 121.1 3.3 13 297.4 4.5 14 121.3 3.4 15 235.9 4.5 16 214.3 3.4 17 80.9 4.5 18 211.3 5.5 19 15.4 7.5 20 156.1 3.6 21 123.6 4.0 22 200.7 8.7 24 18.4 9.0 25 96.5 5.6 26 209.2 4.6 27 212.2 4.3 28 225.9 4.4 1 147.7 3.7 2 91.6 4.4 3 176.4 3.4 4 239.2 3.8 5 266.9 4.7 6 313.4 5.3 7 55.6 5.6 8 253.7 4.1 9 179.6 4.7 10 104.1 4.4 11 73.3 5.0 12 301.4 4.3 13 308.2 4.4 14 228.4 3.8 15 134.3 3.4 16 219.9 3.7 17 59.1 5.7 18 194.6 3.4 19 127.7 3.3 20 248.0 4.1 21 165.4 4.0 22 335.3 8.4 23 68.2 8.3 24 55.5 9.1 25 243.5 4.9 26 170.5 4.0 27 149.3 4.1 28 169.8 4.5 1 230.5 4.6 2 223.1 4.5 3 167.1 7.7 4 334.5 4.8 5 224.3 3.5 6 323.5 4.4 7 78.4 5.2 8 406.7 6.4 9 167.2 3.5 10 173.8 3.2 11 134.0 3.6 12 179.7 3.5 13 31.0 10.4 14 240.5 3.6 1 15 210.1 3.7 1 16 192.0 3.3 1 17 132.8 3.9 1 18 185.4 3.3 19 141.6 3.7 20 71.8 5.5 22 158.2 3.8 3 23 117.0 5.4 3 24 226.5 3.9 3 25 92.6 6.8 -12 1 -12 1 -12 I -12 I -12 1 -12 I -12 I -12 1 -12. 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 111.2 4.7 241.5 4.3 37.7 15.7 251.0 6.3 252.8 8.7 45.0 6.1 155.1 3.2 177.7 3.5 171.9 3.4 190.6 3.4 67.4 5.3 216.7 3.5 293.8 4.5 280.9 4.2 103.0 3.5 105.9 3.9 45.0 7.4 229.0 3.6 89.3 4.9 198.7 3.8 180.9 3.6 17.8 8.4 177.4 10.0 90.0 6.8 193.9 3.6 160.2 3.9 102.3 5.0 267.4 5.6 87.1 6.9 265.4 4.5 137.5 4.1 96.6 3.7 219.3 4.2 181.3 3.3 120.5 5.1 122.2 3.1 146.6 2.9 26.8 10.7 241.4 3.6 57.3 5.6 46.9 6.7 52.0 5.5 292.3 4.2 208.4 3.9 350.3 5.1 157.2 3.3 58.3 7.7 P 83.6 4.7 81.6 5.6 97.4 8.1 140.5 4.6 76.2 6.8 38.0 12.2 126.1 4.1 105.3 6.5 381.1 6.6 303.2 5.6 299.7 5.3 152.0 4.4 182.4 3.7 174.3 3.3 65.0 5.4 89.2 3.8 249.0 3.7 16.2 7.3 0 274.0 4.4 1 138.0 3.6 2 143.5 3.9 3 72.1 6.1 4 180.9 3.6 5 77.5 4.9 6 205.8 3.6 -12 1 -12 I -12 I -12 1 -12 1 -12 I -12 I -12 I -12 1 -12 1 -12 1 -12 1 -12 1 -12 1 -12 I -12 I -12 1 -12 1 -12 1 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 204.9 3.6 100.1 4.2 103.3 4.1 292.8 6.6 53.3 102.5 4.8 66.2 10.2 313.7 5.3 160.6 4.6 106.4 6.6 76.9 86.3 4.4 130.4 3.8 132.7 3.7 114.1 3.3 228.5 3.7 365.6 5.3 89.3 4.6 159.5 3.1 48.4 5.7 209.3 3.4 163.5 3.3 67.3 4.6 223.9 3.7 43.0 8.4 276.1 113.4 3.8 85.3 170.8 3.9 207.7 4.7 106.6 7.6 307.4 136.4 4.1 149.8 4.1 102.5 5.2 53.6 9.8 190.4 110.9 4.3 203.6 3.9 87.0 4.9 196.3 3.1 157.5 68.9 196.0 3.4 317.4 313.2 4.4 197.8 3.4 274.4 238.3 185.0 3.4 81.1 6.3 128.3 3.6 19.9 9.2 225.4 5.6 1 118.9 5.1 174.4 4.1 t 39.9 11.0 1 155.8 3.7 4 98.3 5.1 5 123.6 4.1 121.6 5.2 93.6 6.3 176.4 4.8 77.5 4.4 79.2 5.2 117.8 94.1 3.9 58.3 6.4 76.8 4.3 D 150.5 3.1 1 75.7 2 101.5 3.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/G B98/02542 -64- -12 I -12 I -12 1 -12 1 -12 I -12 1 -12 I -12 1 -12 1 -12 1 -12 1 -12 I -12 1 -12 2 -12 2 -12 2 -12 -12 2 -12 2 -12 2 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12: -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12.

-12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 64.4 5.8 94.5 3.6 86.9 3.9 78.7 4.2 114.5 4.0 59.2 17.0 48.9 9.3 96.7 4.6 178.4 4.2 162.5 4.5 193.8 3.8 38.3 12.0 135.3 4.4 154.9 3.6 170.7 4.5 169.5 3.6 58.0 8.0 181.5 3.3 142.2 3.0 123.4 2.9 240.5 3.8 77.4 4.6 88.8 3.4 88.1 3.6 193.7 3.2 219.8 3.5 244.8 3.8 97.8 4.1 232.4 3.6 233.2 3.9 140.3 5.1 78.1 6.2 135.1 4.1 51.3 11.8 179,0- 3.9- 137.2 4.9 119.0 4.4 167.4 4.5 30.6 10.1 256.3 4.6 23.3 9.9 96.4 3.8 322.8 4.9 99.0 3.7 61.6 5.5 144.5 3.0 118.7 3.2 11.7 5.9 107.8 4.2 154.4 3.1 125.6 3.6 210.6 3.6 19.5 8.7 202.8 7.5 163.9 4.0 141.3 4.1 159.2 3.6 44.1 11.6 107.9 6.6 65.0 6.1 93.8 5.1 385.9 11.2 102.9 3.9 116.5 3.5 68.5 4.5 230.5 4.1 75.2 4.2 71.8 4.4 106.3 3.1 81.8 3.7 26.9 10.1 i 47.7 6.6 -12 22 1 -12 22 I -12 22 1 -12 22 1 -12 22 1 -12 22 1 -12 22 I -12 22 1 -12 22 2 -12 22 -12 22 -12 22 2 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 23 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 24 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 -12 25 113.0 3.3 75.8 4.6 82.8 4.3 127.9 3.7 246.4 13.0 144.6 3.6 165.8 3.5 142.3 3.9 240.9 4.0 123.5 4.2 252.7 4.3 47.4 10.2 181.5 4.0 80.6 4.1 145.2 3.8 95.5 6.9 261.7 5.6 130.2 3.3 217.9 3.6 228.9 3.4 210.2 3.4 161.9 3.0 70.1 4.4 117.0 4.0 104.2 4.0 86.7 4.7 335.2 9.1 21.0 9.2 264.6 4.4 296.6 4.2 110.8 4.1 206.7 4.4 124.4 4.0 62.3 6.8 125.2 4.5 66.7 13.7 177.2 3.9 56.9 5.4 135.5 3.3 100.8 3.2 155.8 4.2 45.1 6.7 114.5 3.1- 106.2 3.5 142.4 3.3 89.3 3.7 91.2 4.7 16.7 8.3 140.7 8.4 87.6 5.1 285.6 4.2 317.9 4.8 28.7 10.8 79.9 5.6 96.5 4.5 130.4 5.0 49.5 12.7 177.6 3.7 108.7 5.0 61.7 6.8 225.7 3.5 40.3 7.9 32.4 8.4 48.6 7.2 80.8 4.1 0 161.1 3.1 1 112.8 3.5 2 279.4 7.3 3 161.6 4.4 4 128.3 4.0 5 20.2 9.3 6 39.5 9.4 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 -12 2 -12 2 -12 2 -12 -12 2 -12 -12 -12 -12 -12 -12 2 -12 -12 2 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 7 222.9 4.1 8 79.0 6.6 9 78.5 5.1 D 60.0 9.7 1 94.1 4.7 91.7 3.1 38.2 7.8 1 34.4 11.0 137.4 5.5 5 101.7 5.0 179.8 3.7 116.8 2.7 8 104.1 3.2 100.0 4.3 0 45.5 10.7 1 202.6 8.7 2 174.1 3.8 3 102.1 3.7 4 266.5 4.0 5 221.8 3.9 6 79.1 5.0 7 218.5 4.0 8 69.2 6.1 9 89.8 5.6 0 105.3 4.3 1 106.0 4.3 Z 68.0 6.2 3 307.3 4.6 1 111.2 3.0 5 196.4 3.7 5 305.2 6.5 8 32.2 12.8 226.6 6.6 0 148.8 3.2 1 103.4 4.4 2 103.3 4.1 3 140.8 3.3 4 117.6 4.1 5 73.1 5.7 6 119.4 4.5 .7 200.7 3.8 18 87.2 5.2 ,9 31.1. 9.9 1 197.4 5.5 2 92.2 8.6 3 42.3 11.0 4 87.3 6.1 5 125.2 12.4 6 192.6 6.3 7 187.2 4.5 9 74.8 4.3 10 290.3 4.2 11 138.0 4.1 12 129.9 3.9 13 142.2 3.9 14 152.0 3.2 15 202.6 4.0 16 103.4 4.3 17 81.3 5.1 18 138.1 4.1 1 85.1 7.8 2 100.5 6.7 3 76.5 18.3 4 195.3 5.9 5 242.9 5.6 6 56.5 5.8 7 15.4 7.6 8 83.3 4.3 9 282.3 4.6 10 210.2 3.4 11 182.1 3.4 12 205.6 4.2 -12 2 -12 2 -12 2 -12 2 -12 2 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 3 -12 2 -12 2 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 -12 83.2 6.6 163.7 3.6 155.6 33.4 11.7 19.5 9.6 122.0 4.4 100.8 5.9 89.3 4.9 139.7 100.6 4.2 27.0 13.1 66.8 7.6 96.4 3.9 166.9 3.1 145.6 3.4 165.2 65.6 5.1 158.6 146.4 221.5 3.7 46.3 11.0 174.7 4.1 215.6 122.4 6.4 198.5 6.6 78.7 5.2 214.1 4.1 88.1 5.9 118.1 4.2 41.1 10.4 106.5 122.7 84.4 177.2 3.7 83.4 4.3 128.8 4.3 207.0 4.3 166.1 34.1 13.4 173.1 5.4 149.5 5.1 125.9 3.2 104.2 64.1 5.6 122.6 3.2 179.1 3.4 1 72.1 133.4 3 128.9 3.8 38.9 11.2 166.4 6.9 43.5 13.6 91.6 7.8 69.0 5.9 150.9 4.1 76.0 5.7 110.6 5.4 P 194.3 3.7 0 49.6 6.9 1 97.7 3.9 2 69.7 8.3 1 46.0 9.2 131.2 3.3 3 73.0 6.3 1 120.0 6.9 5 101.7 6.7 5 14.2 6.9 7 61.1 4.8 8 86.4 6.9 30.1 11.1 1 103.4 6.6 2 188.1 5.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -12 35 3 134.9 4.2 -12 35 4 36.1 15.3 -12 35 5 92.2 7.4 -12 35 6 48.5 8.7 -11 0 1 122.2 7.4 -11 0 3 287.6 5.7 -11 0 4 31.4 15.0 -11 0 5 477.2 10.1 -11 0 6 284.7 15.8 -11 0 8 94.2 14.1 -11 0 9 312.3 6.2 -11 0 10 218.8 5.4 -11 0 11 143.9 5.1 -11 0 12 169.1 4.9 -11 0 13 208.8 6.1.

-11 0 14 393.3 7.6 -11 0 15 144.8 6.1 -11 0 16 11.1 8.2 -11 0 17 84.8 12.9 -11 0 18 104.8 8.1 -11 0 19 158.2 4.5 -11 0 20 257.3 5.7 -11 0 21 74.8 14.4 -11 0 22 293.8 6.4 -11 0 23 29.9 14.4 -11 0 24 165.0 8.4 -11 0 25 151.7 15.3 -11 0 27 21.0 13.9 -11 0 28 35.4 17.4 -11 0 29 73.9 15.3 -11 0 30 74.7 14.2 -11 1 1 392.4 5.9 -11 1 3 27.9 11.5 -11 1 4 171.6 4.0 -11 1 5 94.2 8.6 -11 1 6 506.9 14.1 -11 1 7 185.2 25.1 -11 1 8 505.7 6.3 -11 1 9 120.5 4.8 -11 1 10 346.9 5.6 -11 1 11 233.8 3.9 -11 1 12 386.7 5.0 -11 1 13 626.3 8.7 -11 1 14 173.0 4.1 -11 1 15 114.2 3.9 -11 1 16 250.5 4.1 -11 1 17 180.4 3.3 -11 1 18 110.2 3.3 -11 1 19 181.4 3.3 -11 1 20 265.0 4.2 -11 1 21 96.1 7.7 -11 -1 22 213.0 4.2 -11 1 23 192.6 3.6 -11 1 24 85.7 7.7 -11 1 25 89.5 18.7 -11 1 26 51.3 12.1 -11 1 27 225.6 4.8 -11 1 28 155.8 4.3 -11 1 29 129.3 6.6 -11 1 30 36.1 14.7 -11 2 1 70.0 12.7 -11 2 3 38.3 10.0 -11 2 4 419.7 6.4 -11 2 5 492.1 14.9 -11 2 6 444.8 14.0 -11 2 8 28.5 13.0 -11 2 9 150.4 3.6 -11 2 10 388.5 6.1 -11 2 11 228.4 3.9 -11 2 12 306.9 5.0 -11 2 13 108.2 5.4 -11 2 14 104.5 5.7 -11

-II

-II

-II

-II

-II

-Il -11

-II

-Il -Il -11 -Il -11

-II

-11 -Il -Il -11 -11

-II

-11

-II

-11 -ii -Il -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -ii -11 -11 -ii -11 -11 -11 -11 -11 -11 -11 -11 -11 -Il -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -1! -1] -11 -11 2 15 386.8 2 16 478.0 2 17 190.8 2 18 42.18 2 19 197.2 2 20 253.2 2 21 78.88 2 22 155.3 2 23 216.2 2 24 71.6 2 25 111.11 2 26 157.5 2 27 172.3 2 28 38.6 1 2 29 21.1.8 2 30 29.5 1 3 1 793.2 1 3 3 478.8 3 4 215.4 3 6 720.2 1 3 7 393.1 3 8 453.3 3 9 187.2 3 10 533.6 3 11 415.2 3 12 190.1 3 13 124.5 3 14 156.0 3 15 258.0 3 16 608.7 3 17 199.8 3 1S 162.4 3 19 86.6 3 20 86.0 3 21 224.3 3 22 112.9 3 23 93.5 3 24 84.1 3 25 495.7 3 26 287.6 3 27 30.1 3 28 45.7 3 29 96.8 3 30 90.8 4 1 460.3 4 2 27.2 1 4 3 53.7 1 4 4 220.9 4 5 437.7 4 6 242.2 4 7 160.3 4 8 502.5 4 9 167.2, 4 10 415.7 4 11 246.5 4 12 293.8 4 13 378.2 4 14 186.7 4 15 119.3 4 16 109.8 4 17 245.9 4 18 101.8 4 19 228.0 4 20 183.0 4 21 157.8 4 22 98.6 4 23 129.0 4 24 81.8 I4 25 251.5 I4 26 238.7 I4 27 24.9 1 4 28 238.5 5.9 7.6 4.2 1.1 3.5 3.8 1.8 3.5 3.8 .4.9 7.1 4.4 3.3 4.4 3.7 1.2 5.4 1.5 3.8 6.5 5.6 3.5 8.6 6.4 3.6 3.3 5.4 4.1 9.6 3.5 3.3 4.1 4.7 4.0 4.1 4.6 6.8 7.5 4.5 12.4 12.6 6.0 7.8 7.8 2.3 6.9 8.1 8.7 16.0 3.9 6.2 3.3 6.1 4.0 4.6 5.8 3.8 3.4 4.5 4.5 3.6 4.0 3.4 3.8 4.4 4.5 7.2 9.1 4.5 10.9 4.8 -11 4 29 29.5 12.8 -11 4 30 115.2 6.2 -11 5 1 205.8 6.7 -11 5 3 620.3 21.3 -11 5 4 642.1 14.6 -11 5 5 323.3 10.9 -11 5 6 483.9 12.0 11 5 7 457.3 6.4 -11 5 8 108.1 4.5 -11 5 9 159.3 3.9 -11 5 10 100.4 5.2 -11 5 11 458.0 8.0 -11 5 12 182.5 4.4 -11 5 13 406.0 6.0 -11 5 14 168.2 3.8 -11 5 15 135.1 3.1 -11 5 16 50.5 8.1 -11 5 17 94.4 4.2 -11 5 18 124.2 3.4 -11 5 19 129.8 3.3 -11 5 20 107.5 4.5 -11 5 21 255.6 3.7 -11 5 22 181.0 3.6 -11 5 23 382.6 5.2 -11 5 24 131.2 4.5 -11 5 25 291.2 11.1 -11 5 26 71.8 7.1 -11 5 27 142.5 4.8 -11 5 28 147.3 5.5 -11 5 29 85.4 6.9 -11 5 30 121.1 5.7 -11 6 1 420.0 18.3 -11 6 2 231.2 17.5 -11 6 3 287.9 12.1 -11 6 4 428.5 11.7 -11 6 5 394.5 12.6 -11 6 6 204.2 4.4 -11 6 7 221.3 3.6 -11 6 8 174.8 3.9 -11 6 9 33.5 9.5 -11 6 10 287.8 4.3 -11 6 11 218.8 3.7 -11 6 12 446.4 7.4 -11 6 13 279.7 4.5 -11 6 14 404.3 6.1 -11 6 15 228.9 4.0 -11 6 16 310.3 4.1 -11 6 17 105.9 3.8 -11 6 18 222.6 3.4 -11 6 19 19.2 9.0 -11 6 20 157.8 3.4 -11 6 21 148.0 4.1 -11 6 22 221.5 3.8 -11 6 23 117.2 4.4 -11 6 24 210.9 3.9 -11 6 25 85.8 12.4 -11 6 26 384.5 5.8 -11 6 27 391.3 6.2 -11 6 28 152.9 5.6 -11 6 29 150.9 4.3 -11 6 30 39.1 13.4 -11 7 1 516.7 15.5 -11 7 2 187.9 17.6 -11 7 3 224.5 12.3 -11 7 5 181.9 3.6 -11 7 6 273.0 4.5 -11 7 7 404.0 6.4 -11 7 8 192.6 3.6 -11 7 9 38.2 9.0 -11 7 10 182.8 3.9 -11 7 11 320.1 4.2 -11 7 12 497.4 7.9 -11 7 13 93.3 4.6 -11 7 14 135 .4 3.2 -11 7 15 166.2 3.4 -11 7 16 49.4 -11 7 17 140.4 3.9 -11 7 18 126.0 3.7 -11 7 19 58.2 6.8 -11 7 20 96.1 3.8 -11 7 21 133.2 3.7 -11 7 22 149.6 -11 7 23 154.8 5.8 -11 7 24 352.9 5.3 -11 7 25 77.4 7.7 -11 7 26 16.6 8.1 -11 7 27 48.0 11.3 -11 7 28 45.1 12.6 -11 7 29 91.3 6.4 -11 7 30 213.9 5 *7 -11 8 1 163.7 -11 8 2 26.6 10.9 -11 8 3 187.6 3.9 -11 8 4 67.2 5.9 -11 8 5 481.6 -11 8 6 502.0 7.7 -11 8 7 412.0 -11 8 8 247.7 4.2 -11 8 9 188.0 3.6 -11 8 10 198.8 3.6 -11 8 11 62.5- 5.3 -11 8 12 12037 3.8 -11 8 13 226.2 3.7 -11 8 14 184.8 -11 8 15 273.5 -11 8 16 437.3 6.2 -11 8 17 136.8 4.1 -11 8 18 123.3 3.6 -11 8 19 375.1 5.9 -11 8 20 63.5 5.3 -11 8 21 423.6 6.1 -11 8 22 156.6 -11 8 23 214.9 3.8 -11 8 24 40.2 15.0 -11 8 25 43.6 11.7 -11 8 26 154.4 -11 8 27 255.9 4.6 -11 8 28 100.1 -11 8 29 135.7 -11 9 1 535.1 11.4 -11 9 2 45.8 11.5 -11 9 3 117.5 3.3 -11 9 4 260.9 4.7 -11 9 5 222.3 3.9 -11 9 6 221.0 4.1 -11 9 7 31.6 11.8 -11 9 8 28.7 10.6 -11 9 9 568.8 8.1 -11 9 10 112.3 3.9 -11 9 11 155.3 3.1 -11 9 12 321.3 4.8 -11 9 13 101.8 3.9 -11 9 14 243.9 4.1 -11 9 15 160.5 3.3 -11 9 16 121.2 3.3 -11 9 17 75.8 5.6 -11 9 18 84.4 4.2 -11 9 19 122.6 3.7 -11 9 20 122.8 3.6 -11 9 21 148.1 3.9 -I1 9 22 190.1 4.6 -11 9 23 252.2 4.2 -11 9 24 282.1 6.1 -11 9 25 380.8 7.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 11 9 H1 9 11 9 H1 9 11 10 I11 10 I 1 10 I11 10 I11 10 I 1 10 I 1 10 I 1 10 I 1 10 I11 10 I 1 10 I11 10 I 1 10 I 1 10 I 1 10 I11 10 I11 10 I11 10 I I 10 1 1 10 I 1 10 I 1 10 I11 10 I11 10 1 1 10 I11 10 I 1 10 I 1 10 I11 10 26 272.9 27 112.8 28 212.0 29 155.6 1 475.1( 2 395.8 3 676.8 1 4 228.7 5 325.84 6 273.0 7 220.6 8 375.6 9 339.5 10 94.8 11 157.1 12 206.8 13 48.2 14 46.7 15 74.3 16 122.1 17 118.6 18 172.2 19 112.4 20 98.2 21 21.9 22 69.0 23 150.7 24 312.3 25 108.7 P26 89.1 27'211.0 28 174.6 I29 32.21 1 601.5 2 100.6 3 231.5 4 24.2 358.1 6 254.5 7 145.6 8 323.1 9 225.3 380.5 11 164.0 12 289.6 I13 61.1 14 314.7 95.6 I16 134.7 1 17 104.9 1 18 147.6 1 19 149.1 1 20 159.7 1 21 116.5 1 22 276.1 1 23 15.5 1 24 42.7 1 25 196.8 1 26 138.8 1 27 204.7 1 28 222.9 1 29 41.3 2 1 37.3 2 2 455.4 2 3 400.0 2 4 36.3 2 5 281.1 2 6 577.6 2 7 101.8 2 8 79.0 2 9 324.4 2 10 217.6 1.4 5.2 1.2 5.0 5.7 5.4 0.7 1.9 1.7 5.0 3.9 5.7 5.0 5.5 3.0 3.6 7.9 7.2 5.0 3.9 3.9 3.3 4.4 6.1 9.7 7.1 3.6 8.2 4.9 6.3 4.2 3.9 13.7 8.9 6.4 4.6 5.8 4.3 3.9 5.3 3.7 5.5 3. 3 4.6 5.9 4.7 4.1 3.4 3.4 3.5 3.1 3.3 4.0 5.0 7.8 15.4 4.0 5.6 4.7 4.1 12.1 10.0 6.8 6.2 9.1 4.2 7.8 5.1 5.8 5.2 3.6

-II

-II

-II

-11

-II

-Il -11 -11 -11

-II

-11 -11

-II

-11 -11

-II

-11 -11 -11 -11 -11 -11 -11 -11 -11

-II

-Il -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11

-II

-11 -11 -11 -Il -11 -11 -11 -Il

-II

-11

-II

-11 -11 -11 -11 -1 -1 -1 -1 -1

-I

-1 -1

-I

-1

-I

-1 12 11 1' 12 12 41 12 13 8 12 14 2' 12 15 1: 12 16 3, 12 17 2' 12 18 1' 12 19 1' 12 20 1: 12 21 7; 12 22 1 12 23 8 12 24 8 12 25 1 12 26 2 12 27 1 12 28 12 29 13 1 3z 13 2 21 13 3 3~ 13 4 7 13 5 7 13 6 21 13 7 9 13 8 3: 13 9 2 13 10 13 11 1 13 12 4 13 13 2 13 14 1 13 15 2 13 16 1 13 17 13 18 13 19 13 20 13 21 13 22 13 23 13 24 13 25 13 26 13 27 13 28 14 1 2 14 13 14 3 1 14 4 14 5 1 14 6 2 14 7 2 14 8 2 14 92 14 10 14 11 114 12 I14 13 1 14 14 1 14 15 1 14 16 1 14 17 1 14 18 1 14 19 1 14 20 1 14 21 1 14 24 1 14 25 1 14 26 1 14 27 79.8 02.7 9.9 6 95.0 27.2 52.0 05.4 91.4 09.2 23.4 7.6 6 20.6 16.8 1' 16.5 5 05.5 59.2 51.5 53.08 18.4 1 18.65 14.7 55.2 7.0 4 2.6 5 50.04 3 4 55 .4 19.2 21.3 46.1 05.9 114.6 55.7 159.9 .56.4 92.4 97.8 140.6 148.4 23.7 1 198.4 Z57.8 Z47.1 127.1 152.1 245.1 161.3 :01.8 32.9 15.8 96.1 35.5 112.4 125.3 106.4 160.3 155.5 361.2 381.6 186.5 216.5 15.1 282.3 257.5 110.1 73.0 112.9 55.9 88.1 44.4 214.7 275.2 3.1 5.1 .3 4.4 5.3 5.5 3.6 3.2 4.0 3.4 I.1 4.1 9.8 .9 5.5 4.7 4.9 1.4 2.3 5.2 1.3 5.7 .5 .0 1.5 .8 6.2 3.4 9.1 3.1 5.8 3.9 3.4 5.6 3.2 4.1 3.6 3.7 4.9 10.0 3.8 7.2 4.2 4.0 4.6 5.0 4.2 4.7 5.9 4.1 4.0 3.3 3.8 3.9 3.4 3.9 3.0 5.0 5.6 3.4 3.6 7.3 4.1 3.8 3.6 5.7 5.0 6.6 6.1 10.4 4.0 4.7 -II 1.

-II I -Il I -II I -11 I -II I -Il I -II I -II I -Il I -11 1 -Il I -Il I -11 1 -11 1 -11 1 -11 1 -11 1 -11 1 -11 I -11 1 -11 1 -11 1 -11 1 -11 1 -Il I -11 1 -Il I -11 1 -11 1 -11 I -11 1 -11 1 -11 1 -11 1 -11 1 -11 1 -11 -11 -11 -ii -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -Il -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -Il -11 -11 -Il -11 -11 -Il 4 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 .5 6 .6 .6 6 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 1V 28 76.8 6 1 286.84 2 114.5 3 3 145.5 3 4 242.8 3 5 276.3 4 6 117.1 7 184.0 3 8 279.4 z 9 139.53 10 339.5 11 206.7 12 378.2 13 394.6 14 262.5 15 72.1 16 59.9 17 178.6 18 102.2 19 124.5 20 130.5 21 206.5 22 204.3 23 96.9 24 195.6 25 110.3 26 157.5 27 261.7 28 117.0 1 186.0 2 164.8 3 194.2 4 315.2 5 238.7 6 207.2 7 113.3 8 156.6 9 132.5 10 304.6 11 70.8 12 122.4 13 86.4 14 132.9 15 59.6 16 145.2 17 80.2 18 156.7 19 305.2 20 139.2 21 200.2 22 172.3 23 191.3 24 107.6 25 172.2 26 124.6 527 186.2 11 295.2 7 2 124.8 7 3 143.2 7 4 142.2 7 5 210.1 7 6 183.8 7 7 268.2 7 8 347.0 7 9 337.2 7 10 161.7 7 11 139.3 7 12 175.0 7 13 123.6 7 14 119.6 7 15 88.8 7 16 263.8 1.9 1.3 1.1 1.9 1.2 1.0 1.2 1.2 .8 5.0 3.3 5.1 5.8 4.2 1.8 5.2 3.3 4.0 3.2 3.8 4.6 7.0 5.3 3.7 5.2 5.9 4.6 5.4 4.0 3.5 4.0 5.3 3.7 3.5 3.0 3.1 3.6 5.4 4.2 3.2 5.6 3.6 5.4 3.5 4.8 3.3 4.5 3.2 4.0 4.2 3.9 5.4 4.3 4.4 4.1 4.5 3.5 3.3 3.6 3.3 3.2 3.7 4.9 5.0 3.0 3.0 3.0 3.0 3.4 4.0 3.8 -11 I' -II 1* -II 1~ -Il 1 -II I' -II I -II I -11 I -II I -11 I -II 1 -II 1 -Il I -Il I -II I -11 1 -11 1 -11 1 -II I -11 1 -Il I -11 1 -11 1 -11 1 -11 1 -11 1 -Il I -11 1 -11 1 -Il I -11 1 -II I -11 1 -11 1 -11 1 -11 1 -11 1 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -Il -11 -11 -11 -ii -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -Il

-II

-11 -11 -11 -11 -11 -Il 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 .8 8 18 18 8 18 18 18 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 12 12 2C I2 2 17 281.2 18 100.9 19 91.04 20 82.34 21 196.6 22 85.7 23 137.2 24 54.0 25 133.9 26 104.5 27 35.11 1 103.6 2 178.9 3 228.3 4 35.7 1 5 230.7 6 48.0 6 7 159.3 8 11.3 5 9 143.8 10 44.4 11 236.2 12 324.5 13 43.6 1 14 122.1 15 137.1 16 189.1 17 169.0 18 82.4 19 156.6 20 78.6 21 164.7 22 59.3 23 239.8 24 121.0 25 20.5 26 151.5 1 196.5 2 183.7 3 247.4 4 65.8 5 292.7 6 132.0 7 215.8 8 59.3 I9 74.9 10 235.0 1 Y1 253.5 I12 315.9 I13 132.2 I14 103.3 115 135.0 116 80.9 17 139.5 18 77.9 19 79.6 20 182.2 9 21 152.7 9 22 120.2 9 23 100.4 9 24 189.4 9 26 166.8 0 1 62.4 0 2 247.2 0 3 125.4 0 4 134.5 0 5 127.3 0 6 104.9 0 7 134.5 0 8 172.2 0 9 306.3 0 10 57.6 3.9 3.9 1.9 7.7 7.3 3.7 9.8 6.6 9.2 3.2 3.7 1.6 2.9 '.7 3.1 6.1 3.7 4.8 10.3 4.1 3.6 3.4 3.2 4.6 3.2 7.3 4.1 4.2 4.9 3.8 4.7 5.4 3.4 3.6 5.2 3.7 3.4 3.9 4.1 2.9 3.4 4.4 5.4 5.4 7.3 4.1 4.9 5.2 4.7 4.9 8.1 4.9 3.2 4.4 3.4 3.6 2.9 3.3 4.2 4.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -67- -Il 2 -11 2 -Il 2 -II 2 -11 2 -11 2 -11 2 -ii -11 2 -Il 2 -11 2 -11 2 -11 -ii -ii -ii -11 -ii -11 -11 -11 -11 -11 2 -11 -Il I -ii -11 -ii -11 -11 -11 -11 -11 -11

-II

-11 -11 -11 -11 -11 -11 -Il -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -11 -ii -11 -11

-II

-11 -11 -11 -11 -11 -11

-II

-Il -11 -11 -11 -11

-II

-11 -11 160.0 2.8 102.1 3.2 155.7 3.1 224.5 3.2 163.4 5.1 234.1 3.5 123.9 3.2 285.0 4.2 178.6 11.4 135.2 4.1 32.5 10.6 116.4 3.8 20.2 9.4 65.8 6.7 81.1 6.1 192.5 3.3 85.1 4.0 93.9 6.7 179.9 3.1 131.1 3.3 67.7 4.4 136.8 2.8 119.5 2.8 307.4 4.5 187.7 3.3 65.5 3.8 56.5 5.9 329.1 4.9 142.6 3.1 56.9 5.3 162.9 3.3 158.3 3.9 167.0 4.2 169.3 3.7 82.9 5.7 28.2 11.7 164.2 4.3 68.1 6.4 116.3 4.5 113.8 3.8 228.6 3.6 130.3 3.6 206.3 3.4 35.1 6.9 60.1 4.6 172.9 2.9 145.1 3.5 187.7 2.9 1 359.4 5.5 108.7 4.3 231.5 3.7 135.4 8.5 1170.1 3.0 i160.1 3.3 60.9 5.7 189.6 4.3 3134.5 4.9 39.4 11.1 82.0 5.6 1 231.5 4.8 Z 159.4 3.7 3 38.9 10.5 1 147.9 3.7 232.2 4.3 141.8 5.1 71.4 4.5 196.9 7.1 97.0 3.1 i120.7 3.4 12.7 6.3 1213.2 3.4 170.4 3.1 -11 23 11 -11 23 1 -11 23 1: -11 23 1: -11 23 11 -11 23 1.

-11 23 1i -11 23 1 -11 23 1, -11 23 1, -11 23 2' -11 23 2 -11 23 2: -11 23 2 -11 23 2.

-11 24 1 -11 242 -11 24 -11 24 -11 24 -11 24 -11 24 -11 24 -11 24( -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 24 1 -11 242 -11 242 -11 242 -11 242 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 25 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 -11 26 199.4 3.0 213.2 3.5 89.9 4.1 170.4 3.2 203.7 3.4 57.7 6.9 112.5 3.8 173.5 8.0 51.2 9.3 102.1 4.8 214.9 3.8 15.5 7.7 116.1 4.4 107.3 4.8 117.0 4.4 102.8 3.1 65.8 4.2 276.1 5.1 83.0 3.8 19.2 8.5 210.7 3.6 232.2 3.4 40.0 7.4 93.8 3.5 59.2 5.1 188.7 3.1 104.7 3.1 189.7 3.3 114.9 3.6 75.6 5.6 132.4 11.0 199.5 4.0 66.9 5.6 171.0 3.5 16.1 7.9 176.5 3.7 137.2 3.9 132.8 3.8 108.4 5.6 108.5 3.1 155.5 3.5 162.7 4.9 388.8 6.0 356.7 5.0 134.3 2.9 158.4 3.5 85.7 3.3 42.0 6.9 1 79.7 5.4 Z 136.9 2.9 3 238.1 4.1 4 203.1 4.3 5 79.7 9.4 5 84.7 4.1 7 112.7 4.0 9 65.8 8.5 9 85.7 4.5 D 56.4 7.9 1 170.6 4.3 2 81.8 4.7 i102.3 4.9 141.7 4.8 196.6 6.2 1 396.7 6.4 5 151.5 3.5 5 131.1 2.7 7 245.9 3.4 3 140.6 4.0 115.0 2.9 0 60.2 5.5 1 148.3 3.6 2 104.7 3.7 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -I1 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 -11 2 6 6 6 6 6 6 .6 .6 .6 .6 '7 .7 .7 .7 .7 .7 .7 .7 .7 .7 .7 .7 17 17 17 17 17 17 17 Z7 27 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 28 29 29 29 29 29 29 29 29 29 25 25 2' 2' 2' 2' 3' 3' 3' 13 126.6 14 137.5 15 270.4 16 70.36 17 105.2 18 170.3 19 125.6 20 104.5 21 33.2 1 22 50.7 1 1 253.41 2 34.9 12 3 104.4 4 263.4 5 31.7 1 6 97.6 3 7 178.4 8 61.8 5 9 227.0 10 158.0 11 208.8 12 251.0 13 167.4 14 199.9 15 140.! 16 248.6 17 219.1 18 85.0 19 222.8 20 98.8 21 116.0 1 102.7 2 207.0 3 211.6 4 89.8 5 91.1 6 135.0 7 111.1 8 98.02 9 15.5 10 289.4 11 95.3 12 176.2 13 101.9 14 158.5 15 206.4 16 80.9 17 93.0 18 176.1 19 210.9 20 75.9 1 156.4 2 183.4 I3 64.0 5 191.1 I6 88.8 7 132.3 8 225.4 9 53.4 10 127.2 11 92.2 )12 112.3 13 130.3 9 14 58.8 9 15 189.6 9 16 234.4 9 17 39.1 9 18 118.8 9 19 91.3 0 1 248.5 0 3 264.4 0 4 227.5 7.7 4.2 4.0 i.2 5.5 3.3 3.8 4.4 1.2 0.8 1.5 1.8 1.2 t.2 1.2 .4 2.9 .4 3.3 2.9 3.7 6.7 3.4 3.6 3.2 4.1 3.8 5.6 5.2 4.3 6.3 2.8 4.0 3.6 1.3 t.8 4.1 3.7 3.2- 7.6 7.0 4.6 3.3 4.1 3.7 3.7 5.9 4.3 3.8 4.4 7.3 3.0 4.0 5.3 4.0 5.6 6.6 7.3 5.8 3.1 4.0 3.4 4.0 6.9 3.4 3.6 10.1 3.8 6.0 10.5 12.2 7.4 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 3 -11 2 -11 3 -11 2 -11 2 -11 3 -11 3 -11 3 -11 3 -113 -11 3 -11 1 -113 0 0 0 0 0 0 0 0 0 0 0 ~0 .0 .0 31 31 31 32 31 31 32 32 32 31 31 31 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 33 33 33 33 33 32 32 32 32 32 32 32 32 3' 3' 3 3 3 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2 3 5 6 7 8 9 10 11 12 13 14 15 16 17 2 3 4 5 6 7 8 9 10 11 12 12 2 3 '4 '5 6 '7 31 31 31 1 1 4I 4, 4: 4' 41 41 41 5 155.0 103.3 50.2 6 109.5 211.9 65.3 174.0 17.8 13.1 107.2 62.6 64.8 77.1 47.9 1 13.87 19 1.7 56.8 1 63.75 100.6 229.4 59.8 210.2 71.1 138.3 123.6 168.6 201.6 57.5 129.2 61.2 220.-8 53.0 1 75.4 1 111.8 119.0 108.7 99.5 47.9 35.9 153.6 58.7 114.2 3134.8 3204.6 533.0 97.6 75.1 188.8 135.2 58.7.

53.4 41.6 103.7 68.8 0 103.6 1 54.6 2 62.8 3 51.7 4 14.6 185.7 184.4 3106.1 t 118.1 5 80.7 6 30.7 7 90.8 8 49.2 9 60.2 0 70.4 1 98.4 2 75.4 1 108.7 8.9 5.7 .3 3.7 8.4 3.8 5.8 5.1 2.4 1.3 9.1 4.1 1.8 3.4 3.4 4.1 3.8 7.1 3.6 5.4 1.6 0.6 3.2 3.8 4.8 5.1 6.7 9.1 3.2 4.2 3.6 3.7 3.6 10.7 12.1 8.3 3.4 4.1 3.8 7.2 7.3 4.3 5.1 5.4 6.1 7.4 12.6 3.9 7.6 5.2 5.4 5.9 5.8 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -68- -II

-I

-I0 -I0 -I0

-I

-I0 2 91.4 5.8 3 119.2 4.3 4 190.9 5.6 5 207.0 6.2 6 160.3 4.6 7 84.0 10.1 8 96.7 7.4 9 40.4 10.0 10 170.2 4.1 1 67.1 13.6 2 178.1 3.6 3 87.5 7.9 4 131.5 5.4 5 92.1 6.6 6 47.3 13.1 7 19.9 9.7 I 44.0 17.9 2 438.6 8.4 3. 477.7 8.8- 4 173.5 4.4 5 206.3 4.8 6 108.3 6.2 7 278.3 6.5 8 395.5 7.5 9 200.0 4.9 10 294.9 10.5 11 126.3 4.5 12 121.1 11.4 13 216.5 7.4 14 74.1 6.9 15 357.9 6.8 16 222.7 5.2 17 97.1 5.8 18 394.2 7.4 19 161.3 5.3 20 20.4 12.7 21 254.0 5.9 22 223.4 5.5 23 213.5 5.1 24 30.1 15.1 25 17.1 11.8 26 179.4 18.2 27 177.3 5.4 28 97.1 7.6 29 125.3 7.9 30 121.8 13.0 31 16.0 11.4 1 20.0 9.7 2 17.7 9.0 3 569.2 7.7 4 430.5 5.5 5 133.3 3.5 6 340.3 4.2 7 352.4 5.0 8 328.5 4.7 9 340.7 5.2 10 314.5 6.6 11 160.6 3.3 12 155.0 6.5 13 105.6 5.9 14 260.7 4.2 15 291.6 4.2 16 157.6 3.6 17 134.0 3.4 18 235.7 3.6 19 138.1 3.9 20 55.7 6.6 21 135.5 3.3 22 170.2 3.4 23 131.0 3.5 24 193.6 3.6 25 166.4 3.9 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 224.2 11.8 106.1 6.8 207.8 4.3 181.6 4.4 62.8 9.1 75.3 7.1 342.6 5.1 346.1 4.4 366.3 5.2 584.4 7.7 239.9 3.8 661.1 8.0 296.7 4.6 507.6 6.7 570.6 10.2 739.5 12.7 707.2 11.3 431.8 6.4 188.3 4.4 185.6 3.6 239.0 3.7 176.9 3.6 299.2 4.2 145.6 3.7 291.9 3.9 57.2 7.2 407.5 6.1 77.1 6.0 219.0 3.9 218.5 4.0 163.0 4.1 247.4 12.9 283.3 4.7 1 69.1 8.6 165.8 4.6 138.1 4.9 1 55.7 9.0 370.4 5.8 829.4 14.6 438.9 6.2 368.5 4.9 454.4 6.8 315.7 4.5 136.0 4.7 83.3 4.3 446.1 7.2 0 387.6 8.5 1 310.2 5.2 2 101.5 4.3 3 122.9 5.0 4 78.1 4.8 5 112.3 4.1 6 219.6 3.8 7 443.7 5.8 8 242.9 3.9 9 217.8 3.4 0 134.3 3.5 1 232.0 3.8 2 197.7 4.2 3 251.1 3.9 4 56.0 7.7 5 357.7 4.7 6 273.8 7.6 7 121.8 4.8 .8 82.5 7.2 -9 105.1 6.0 0 133.7 5.2 .1 328.4 5.5 1 88.7 3.7 2 331.2 4.5 3 138.1 3.5 4 866.2 11.7 -10 -10 L -10 z -10 -10 z -10 L -10 z -10 -10 -10 L -10 -10 -10 -10 -10 -10 -10 -10 -10 10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 603.4 8.7 563.7 9.0 500.2 7.1 399.4 6.4 228.5 10.2 38.1 15.1 105.6 4.0 623.4 9.6 137.7 3.9 171.0 3.4 230.3 3.7 153.3 3.5 198.6 3.4 174.0 3.5 391.3 5.0 135.5 3.6 179.9 4.0 79.0 7.5 193.9 4.0 48.1 9.1 200.0 3.9 224.4 6.7 153.5 4.1 111.6 6.0 76.1 7.5 135.3 5.8 216.3 3.4 263.0 4.0 194.6 3.8 398.5 5.6 22.4 10.7 344.0 5.4 648.6 9.4 240.5 3.7 539.6 7.8 I 253.9 3.7 343.2 5.5 245.5 4.5 104.4 4.6 209.1 3.7 318.8 4.9 171.7 3.4 220.6 3.7 1 141.6 3.3 72.6 5.6 368.0 4.7 1 112.2 4.7 264.0 4.1 252.4 3.9 4 101.3 4.7 5 64.5 7.7 5 288.2 6.4 7 202.4 4.5 8 89.6 7.3 113.4 5.3 61.8 12.5 1 324.7 5.6 618.5 8.0 362.2 5.4 53.5 6.9 227.4 4.0 473.0 6.0 292.3 5.0 259.4 3.8 1 303.2 6.4 89.0 18.6 0 269.5 4.2 1 355.9 5.8 2 255.0 4.4 3 51.0 6.7 4 366.4 6.4 5 284.6 4.6 -10 -10 -10 -10 -10 -10 -10 -10( -10( -10 -10 -10 -10 -104 -104 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -to -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -t0 -10 -10 -10 -10 -10 -10 -0 -10 -10 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 2 3 4 :5 6 18 1 9 8 1 8 2 8 1 8 14 8 1 8 lfi 8 17 8 24 8 2 8 2 82 8 2' 8 2.

8 2 116.6 175.3 127.3 289.8 311.1 186.0 57.8 22.8 I 80.4 296.7 199.5 304.2 149.4 144.7 129.8 69.7 84.0 5 231.3 333.8 363.6 94.5 318.1 625.7 556.0 1 179.6 188.5 61.0 115.7 299.7 267.4 162.7 101.6 308.6 364.4 224.4 123.3 168.6 270.4 226.4 132.1 100.8 161.0 16.7 159.6 71.9 54.3 349.7 283.2 121.4 373.0 227.2 260.1 200.1 80.9 80.9 301.1 1 66.7 331.8 3 101.2 t 34.1 5 169.7 6 109.4 7 346.1 8 268.2 9 148.8 0 173.8 1 49.8 2 86.8 3 110.7 4 260.8 5 195.2 6 163.3 3.6 3.9 4.2 4.3 3.4 6.8 0.2 6.2 4.7 7.6 5.4 4.8 4.6 8.9 .7 4.6 4.8 5.2 7.1 4.7 7.8 10.1 3.6 3.3 6.3 4.1 4.2 3.3 5.1 4.7 5.2 3.8 3.4 4.2 3.8 3.8 8.2 4.3 11.2 6.8 5.4 5.3 3.7 3.7 10.2 6.2 4.1 5.2 6.6 3.8 12.1 3.4 5.6 3.7 3.2 8.1 4.9 4.3 4.1 4.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 1 1 i -t0 27 28 29 30 2 3 4 5 6 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 12 '3 15 17 19 2 1 3 2 3 2 D32 0 2 0 3 1: 1] 11 146.3z 345.5 146.3 119.0 312.0 6 400.6 6 297.3 4 139.4 3 370.2 5 180.2 1' 321.7 4 602.5 9 193.4 288.1 387.6 384.2 231.3 22.4 9 26.8 1I 252.4 135.2 89.1 4 202.0 227.1 252.0 71.9 19 1.2 286.6 343.2 195.9 115.2 44.5 1 124.8 494.5 112.8 262.1 624.4 412.3 451.7 294.9 178.8 0 149.5 1 455.5 2 338.4 3 419.4 4 312.4 5 194.7 6 317.1 7 135.3 8 216.9 9 143.4 0 139.4 1 197.0 2 64.7 3 81.5 4 70.1 5 297.8 6 206.4 .7 95.8 .8 431.3 ~9 35.8 .0 43.8 3 436.2 4 511.8 5 293.9 6 276.0 7 287.1 8 312.2 9 196.4 10 128.2 11 324.9 12 16.6 1.4 .4 1.6 1.8 .3 .0 .2 .7 .0 4.1 .5 '.2 3.5 4.8 5.3 6.7 3.9 .6 0.8 4.1 3.4 .2 3.6 3.6 4.7 3.6 6.9 5.0 4.3 4.9 3.8 4.6 10.0 4.2 3.9 8.6 13.5 6.5 4.1 3.6 3.6 7.0 5.4 5.7 4.5 3.4 5.2 3.4 3.6 3.4 3.5 3.5 5.7 5.0 6.5 8.2 4.4 5.4 6.3 12.7 11.4 9.4 16.9 5.6 4.4 4.0 4.8 4.2 4.7 4.8 7.8 -10 11 1 -10 11 1 -10 11 1 -10 11 1 -10 11 1 -10 11 1 -10 11 1 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 2 -10 11 3 -10 12 -10 12 -10 12 -10 12 -10 12- -10 12 -10 12 -10 12 -10 12 -10 12 1 -10 12 1 -10 12 1 -10 12 1 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 12 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 -10 13 159.9 3.4 157.2 3.5 268.6 5.1 142.4 3.4 218.4 3.5 285.4 4.2 120.4 3.4 189.3 3. 5 251.0 3.8 15.6 7.7 273.6 4.4 84.7 9.8 124.2 6.7 337.3 5.3 85.9 6.8.

77.6 7.9 122.2 4.9 110.0 5.7 650.4 16.1 111.9 5.1 125.9 3.4 379.9 5.6 356.3 4.9 175.1 3.3 337.3 5.6 153.7 3.0 125.6 3.3 1 523.8 7.6 333.7 4.9 256.9 4.8 1 63.6 6.3 1 60.6 4.9 i89.9 5.4 i325.1 4.1 1 182.0 3.3 221.2 3.4 197.0 3.3 181.8 3.7 1 189.2 3.9 Z 119.8 5.3 3 77.0 5.1 4 126.5 7.2 5 101.5 5.3 5 234.6 4.4 7 188.1 4.2 8 77.7 6.5 9 183.7 4.0 318.1 4.8 487.5 8.4 1108.1 4.8 1 322.4 5.0 i452.7 7.1 i384.4 5.5 1 199.9 3.5 3 11719 4.2 )502.4 7.0 0 337.1 4.9 1 247.2 3.9 2 186.8 3.5 3 228.8 3.5 4 240.3 4.1 5 34.4 9.6 6 261.7 4.0 7 302.7 4.9 .8 195.2 3.3 S9 191.1 3.9 !0 133.1 3.5 1 225.0 3.8 !2 15.8 7.8 B3 207.4 3.6 M4 198.8 8.0 Z5 214.1 3.9 -10 1 -10 1.' -10 1' -10 1 -10 P -10 P, -10 1' -10 1, -10 1, -10 1, -10 1' -10 1, -10 1, -10 1, -10 1, -10 1, -10 1, -10 1, -10 1, -10 11 -10 11 -10 1.

-10 1.

-10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -101 -101 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 26 255.6 4.3 27 223.6 4.3 28 126.5 5.3 29 202.2 5.0 1 488.6 8.6 2 456.3 7.0 3 259.8 4.6 4 133.5 3.8 5 131.7 3.9 6 105.7 3.5 7 331.3 5.0 8 55.4 6.2 9 255.8 4.1 10 102.6 4.8 11 125.2 3.1 12 97.2 4.4 13 338.0 5.3 14 65.9 5.4 15 255.8 4.2 16 125.3 3.6 17 95.0 3.3 18 253.3 4.1 19 473.4 6.7 20 291.5 5.0 21 22.0 9.9 22 35.9 10.2 23 107.0 5.0 25 294.7 4.3 26 124.5 4.4 27 231.4 4.7 28 131.5 4.7 29 117.1 6.1 1 426.6 7.4 2 291.2 5.3 3 426.0 8.1 4 576.1 9.3 5 245.6 3.7 6 169.9 3.0 7 597.5 9.1 8 380.0 5.2 9 101.2 4.0 10 82.7 4.2 11 255.9 3.7 i12 281.7 4.0 ;13 245.7 3.9 i14 280.4 4.6.

i15 155.0 3.1 516 110.4 4.3 517 97.9 3.9 5 18 32.6 11.7 5 19 70.9 5.0 5 20 98.5 4.5 5 21 94.9 4.4 5 22 165.8 3.4 5 23 152.4 8.9 5 24 155.3 3.7 5 25 286.1 4.5 5 26 88.7 5.3 5 27 189.3 3.9 5 28 83.3 8.0 6 1 175.6 5.6 6 2 302.9 5.8 6 3 213.2 5.1 6 4 238.5 3.6 6 5 297.7 4.8 6 6 115.8 3.4 6 7 98.6 4.2 6 8 257.3 3.9 6 9 322.7 4.5 6 10 83.5 4.1 6 11 232.7 3.7 6 12 308.6 4.2 -10 N~ -10 U( -10 U -10 1 -10 1 -10 1( -10 1 -10 1 -10 14 -10 14 -10 14 -10 14 -10 14 -10 1i -10 1i -10 1i -10 1* -10 1' -10 1' -10 1 -10 1 -10 1 -t0 1 -t0 I -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 I -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 1 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -t0 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -t0 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 .7 .7 .7 17 17 18 18 18 01 13 154.2 14 2 13.9 15 148.2 16 49.45 17 78.73 18 50.7 19 196.5 20 139.2 21 126.2 22 161.7 23 179.5 24 175.1 25 113.7 26 186.8 27 149.7 28 17.4 1 109.4 2 161.4 3 205.4 4 73.7 4 5 266.4 6 96.0 3 7 180.7 8 88.63 9 442.1 10 102.0 11 92.9 12 54.6 13 305.0 14 68.9 15 128.9 16 186.8 17 146.3 18 263.3 19 128.1 20 163.2 21 100.4 22 134.6 23 26.0 24 286.9 25 81.7 26 273.1 27 50.7 28 18.2 1 372.7 2 233.6 13 342.8 14 189.6 15 114.5 86 127.5 8 7 217.2 8 8 117.6 8 9 134.6 8 10 416.6 8 11 122.5 8 12 143.9 8 13 89.7 B 14 145.1 8 15 77.1 8 16 89.8 8 17 266.5 8 18 22.1 8 19 253.6 8 20 187.8 8 21 170.1 8 22 247.5 8 23 139.8 8 24 59.2 8 25 112.9 8 26 29.3 8 27 71.9 9 1 302.2 3.1 3.2 3.6 .8 1.9 1.4 3.4 3.4 3.9 4.3 6.6 4.2 4.2 5.3 5.2 3.6 .3 3.9 .9 3.3 .4 6.2 3.4 4.9 5.2 4.4 4.3 3.1 3.9 3.2 4.8 3.3 3.9 8.1 10.9 4.8 6.3 10.0 6.2 3.8 6.2 3.1 2.9 3.1 3.4 3.1 6.2 2.9 3.2 3.8 3.9 3.8 9.4 3.9 3.8 4.1 5.1 4.2 7.9 4.6 11.4 6.8 4.6 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/G B98/02 542 19 -t0 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 '20 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 2 333.1 3 182.6 4 71.0 3 5 226.7 6 302.3 7 215.3 8 152.5 9 181.3 10 72.4 11 393.5 12 150.1 13 19.1 14 231.3 15 156.4 16 281.0 17 142.9 18 150.0 19 250.3 20 126.4 21 225.0 22 94.9 23 113.6 24 40.9 1 25 261.7 26 64.5 27 38.61 1 400.0 2 101.9 3 223.8 4 278.6 5 218.6 6 62.5 7 253.9 8 80.4 9 79.7 10 174.8 11 175.5 12 249.6 13 69.5 14 210.7 15 81.7 16 128.0 17 22.3 18 152.6 19 57.8 20 125.8 21 105.7 22 88.0 23 105.0 24 144.9 25 143.1 26 20.8 1 159.6 2 223.4 3 74.8 4 116.7 5 267.6 6 139.3 7 172.0 8 137.2 9 90.6 10 118.6 11 461.5 12 109.0 13 159.3 14 129.0 15 114.9 16 122.6 17 247.2 18 414.7 I19 119.9 I20 185.9 5.6 4.8 .6 3.4 4.6 3.3 3.0 3.0 4.8 5.2 2.9 8.1 3.6 3.1 4.3 3.2 3.2 3.5 3.5 7.6 6.1 4.0 4.3 7.4 12.8 7.7 4.8 3.6 4.0 3.9 t.6 4.0 t.0 3.6 3.0 3.0 3.3 4.9 3.2 4.6 3.4 10.0 3.2 6.2 4.5 4.3 5.4 4.5 3.9 4.1 9.5 3.6 3.7 7.5 3.3 3.9 2.7 3.0 2.8 3.2 3.4 6.0 2.8 2.9 3.0 5.1 3.2 3.8 5.3 3.7 9.0 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -102 -102 -102 -102 -102 -102 -102 -t0o -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 21 22 23 24 25 26 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 2 3 4 5 6 7 8 9 10 11 12 13 15 2' 2 2: 1 2: 2I 1 2 1 2 t 3 1 4 125 4 1 4 1 4 1 4 1 4 1 239.5 45.28 68.62 92.9 136.1 40.8 1 119.2 247.1 161.3 121.5 60.4 4 81.8 3 45.4 5 275.3 249.6 2 10.6 94.7 137.3 139.8 84.8 289.1 147.3 123.4 208.0 253.4 180.2 157.1 100.4 93.6 84.2 173.8 316.0 176.6 164.1 157.9 196.1 139.3 331.1 161.9 78.6 I15.5 39.9 202.1 1112.0 I108.4 308.9 80.4 1109.3 8146.0 )160.4 0 253.7 1 34.6 2 93.6 3 187.5 4 155.3 5 93.1 140.1 1216.0 216.3 I32.5 106.4 88.3 1127.0 194.9 )83.8 0 115.3 1 92.5 2 275.8 3 220.6 4 154.2 5 171.5 6 227.1 3.8 1.3 1.1 1.8 4.6 2.6 !.8 1.3 1.0 .7 .5 .8 3.9 4.0 3.1 3.2 2.8 3.0 3.8 5.0 3.2 3.1 3.6 6.4 3.5 3.5 4.7 4.8 6.2 3.7 6.2 3.7 3.6 4.3 3.0 2.8 4.5 2.8 3.7 7.1 7.9 3.1 3.2 4.4 4.0 3.7 9.0 3.4 4.0 10.8 4.5 3.7 4.0 5.1 4.6 4.1 4.1 8.9 2.5 2.9 2.7 2.8 4.1 3.5 2.9 4.0 3.3 3.1 3.2 3.6 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -10 2 -102 -10 2 -10 -10 2 -10 2 -10 2 -10 2 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 -10 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5S '5 '5 .5 :5 5 :5 15 15 15 15 15 15 15 16 16 16 16 16 16 M6 26 M6 26 26 26 26 26 26 26 26 26 26 26 26 26 26 27 27 27 27 27 27 27 27 27 27 27 27 27 27 27 2', 2' 2' 17 114.5 18 212.2 19 185.4 20 256.0 21 66.77 22 192.5 23 25.2 1 24 135.6 1 125.24 2 211.7 4 3 219.33 4 129.8 6 5 382.96 6 106.5 7 140.3 8 129.2 9 108.9 10 45.45 11 294.7 12 182.1 13 205.6 14 185.8 15 18.1 16 252.3 17 151.2 18 282.7 19 141.6 20 136.0 21 104.3 22 14.2 23 85.5 1 118.4 2 74.66 3 21.3 1' 4 206.6 5 79.04 6 112.9 7 153.2 8 43.8 9 60.65 10 161.8 11 51.2 12 162.6 13 138.9 14 51.5 15 161.7 16 268.7 17 153.4 18 103.5 19 71.8 20. 146.8 21 106.2 22 105.1 23 28.5 1 45.6 2 158.0 3 98.1 4 185.0 5 135.0 6 208.9 7 89.6 8 128.8 9 107.0 10 139.5 11 72.2 12 163.9 13 71.2 14 243.9 7.0 4.6 3.7 4.5 4.3 1.1 3.7 .3 I. 1 .7 1.8 1.8 1.9 1.9 3.9 4.0 3.3 3.2 3.2 8.4 5.6 4.0 4.0 3.2 3.4 4.2 7.0 5.2 2.8 ~.0 0.4 4.7 .6 3.3 2.7

I

3.0 2.8 6.3 3.5 3.2 6.5 10.3 4.4 3.6 3.7 6.0 3.5 4.0 4.2 10.2 5.1 3.3 5.4 3.1 3.2 3.3 3.3 2.8 2.8 3.5 3.6 2.9 5.6 7.8 4.1 4.1 3.4 4.4 -10 27 1 -10 27 2 -10 27 2 -10 27 2 -10 28 -10 282 -10 28 -10 28 -10 28 -10 28 -10 28 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 1 -10 28 2 -10 282 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 291 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 29 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 30 -10 31 -10 31 -10 31 -10 31 -10 31 -10 31 -10 31 -10 31 119.4 3.9 67.4 5.7 174.1 3.3 66.6 5.6 159.0 4.8 22.7 10.4 104.5 5.3 182.5 3.4 66.7 4.3 194.8 3.1 127.4 3.1 101.4 3.4 70.8 4.9 111.4 2.8 202.4 4.2 108.5 6.3 260.6 6.1 100.1 4.2 177.1 3.2 95.0 3.9 122.4 3.7 136.3 4.8 177.3 3.4 43.9 76.6 5.9 60.9 5.7 237.1 5.2 151.7 3.2 135.9 4.8 144.9 4.3 62.5 3.8 19.3 148.7 3.3 68.3 3.6 134.8 3.2 264.1 6.9 116.2 116.2 3.3 165.2 3.4 122.6 3.4 191.4 4.3 196.6 3.9 34.6 9.6 234.7 3.9 90.4 5.1 117.3 3.6 44.4 176.6 140.9 4.6 77.5 6.9 111.6 3.2 12.1 6.1 92.0 6.9 205.6 8.3 )145.2 3.1 1 105.0 3.9 2 90.9 3 20.4 4 79.9 4.7 5 62.5 6.2 6 70.3 7 48.8 7.7 8 54.7 6.6 9 97.3 4.4 115.8 7.7 121.8 10.7 t 108.1 5 155.0 8.3 5 170.9 7 210.7 9 262.4 3.6 D 87.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -71 2 2 2 2 2 2 -to -10 108.8 3.5 121.5 4.4 115.9 4.2 155.2 3.4 238.2 3.8 159.0 3.1 47.8 8.9 90.9 4.8 77.5 5.6 16.2 8.2 17.3 8.6 17.8 8.1 270.5 5.0 228.1 4.3 142.5 2.9 229.1 3.7 160.4 3.9 126.1 3.3 61.3 5.6 111.1 3.4 131.4 3.9 38.1 13.0 73.2 4.7 71.0 5.7 153.3 5.6 88.2 7.4 58.7 9.5 95.4 5.2 39.5 6.4 41.5 14.2 179.7 4.0 70.4 4.5 80.2 3.9 163.7 3.1 162.8 3.1 205.2 3.6 139.5- 3.1 49.0 6.7 80.3 4.6 91.3 4.3 37.2 12.3 90.8 6.3 197.4 8.1 309.8 7.3 227.1 4.5 97.7 5.7 111.5 4.7 55.9 4.9 111.8 4.0 89.8 4.4 154.4 3.0 74.8 5.4 1 61.8 5.8 1 73.2 5.1 85.7 6.6 118.1 5.5 106.8 5.7 49.8 11.1 140.0 4.0 41.1 11.9 44.2 10.5 134.7 4.0 137.6 3.0 D 86.5 3.9 1 86.6 5.0 2 18.9 8.2 24.5 10.8 95.9 6.1 80.5 7.5 1 10.1 5.1 5 14.6 7.2 6 145.8 4.7 -10 2 -10 -10 2 -10 2 -10 -10 2 -10 2 -10 2 -10 -10 -10 2 -10 -10 -10 -10 -9 4 -9 I -9 I -9 I -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 7 101.5 8.7 8 57.3 7.5 9 25.0 9.1 10 84.1 4.5 1 134.0 7.0 2 37.9 11.7 3 111.4 5.4 4 126.5 4.6 5 241.7 4.2 6 103.2 5.4 7 144.5 4.9 8 91.0 5.4 1 195.0 5.6 2 152.7 5.9 3 134.9 4.9 1 14.0 10.4 2 794.2 14.7 3 149.2 4.2 4 855.3 16.0 5 273.6 5.6 6 350.7 7.7 7 220.2 6.9 8 8.4 6.2 9 745.2 11.5 10 268.8 5.5 11 271.3 5.3 12 138.4 16.0 13 93.3 8.0 14 77.0 9.0 15 28.9 13.5 16 452.7 10.5 17 150.3 4.7 18 183.4 7.3 19 545.9 12.4 20 49.7 12.7 21 300.5 6.3 22 48.2 16.6 23 127.8 4.8 24 15.5 10.8 25 94.5 6.4 26 118.1 6.2 27 262.7 9.9 28 47.0 19.3 29 97.9 6.9 30 120.0 7.4 31 146.5 6.0 32 146.5 6.0 1 365.2 10.5 2 315.3 4.8 3 592.8 7.6 4 183.2 3.5 5 22.2 10.2 6 449.9 6.8 7 243.4 3.3 8 587.2 7.7 9 666.8 7.5 10 210.1 4.3 11 180.9 3.8 12 357.6 7.3 13 238.2 4.0 14 593.1 9.5 15 436.6 7.0 16 275.9 4.7 17 286.3 4.4 18 291.7 5.5 19 16.0 7.7 20 217.8 3.7 21 325.4 4.7 22 106.2 4.5 1 23 96.2 4.7 1 24 113.6 3.9 I 25 111.4 4.8 -9 I -9 1 -9 I -9 1 -9 1 -9 1 -9 1 -9 2 -9 -9 -9 2 -9 -9 2 -9 2 -9 -9 -9 -9 2 -9 2 -9 2 -9 2 -9 2 -9 2 -9 2 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 26 97.7 4.7 27 269.7 7.5 28 189.6 5.1 29 120.2 4.1 30 218.9 4.4 31 173.9 6.5 32 125.7 5.3 1 119.7 4.6 2 329.1 4.8 3 225.6 3.3 4 321.2 4.4 5 497.1 5.9 6 217.3 3.6 7 195.3 3.2 8 618.0 8.2 9 498.3 5.5 10 504.0 6.9 11 257.5 3.9 12 791.8 10.5 13 147.9 3.8 14 642.2 12.4 15 156.6 3.4 16 310.8 5.3 17 275.4 4.2 18 164.4 3.8 19 165.5 3.5 20 291.6 4.7 21 132.5 3.9 22 74.6 5.8 23 219.9 3.7 24 154.4 4.2 25 102.4 4.7 26 81.8 6.0 27 309.1 6.6 28 91.2 8.5 29 130.2 4.3 30 161.2. 4.5 31 185.0 4.1 32 82.8 7.2 1 91.9 8.0 2 248.3 3.8 3 60.1 4.8 4 391.7 5.5 5 497.4 5.7 6 947.7 14.3 7 165.3 3.0 3 8 111.0 3.4 1 9 497.6 5.8 1 10 342.6 5.0 11 438.8 8.1 12 329.4 6.0 3 13 103.6 3.7 3 14 295.5 5.2 15 75.2 5.8 3 16 410.0 6.4 3 17 287.5 4.2 3 18 140.3 4.9 3 19 199.7 3.8 3 20 142.3 3.4 3 21 97.0 4.2 3 22 261.5 4.0 3 23 86.1 4.1 3 24 167.2 3.4 3 25 267.5 4.2 3 26 35.0 12.2 3 27 301.1 6.4 3 28 48.6 11.7 3 29 29.8 11.1 3 30 222.7 4.3 3 31 116.9 4.7 3 32 316.9 6.0 4 1 380.3 5.7 -9 4 -9 4 -9 4 -9 4 -9 4 -9 4 -9 4 -9 4 -9 4 -9 4 -9 4 -9 Li -9 4 -9 4 -9 4 -9 ,i -9 ,i -9 ,i -9 ,i -9 z -9 -9 z -9 z -9 -9 .9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 62.3 4.4 437.0 7.6 517.3 208.0 99.0 3.3 459.3 6.6 380.8 4.6 264.9 3.9 0 260.5 4.3 1 230.6 3.8 Z 260.6 6.8 3 260.3 4 683.7 11.6 5 125.9 3.7 5 241.2 3.8 7 383.2 8 131.3 4.2 282.2 4.3 D 184.2 3.3 1 280.0 4.3 2 104.4 4.2 3 245.0 4 280.6 4.4 5 225.1 6 106.3 4.6 7 202.8 8.2 8 125.9 7.6 9 123.2 4.1 0 190.2 4.3 1 137.8 1 454.9 6.8 Z 198.3 3.7 390.8 5.4 t 181.3 5 760.7 .10.4.- 5 365.7 4.6 7 509.3 7.7 3 229.6 3.3 275.7 0 499.3 7.4 1 327.5 4.6 2 562.8 7.9 3 235.8 3.9 4 153.4 3.4 5 147.1 3.7 .6 482.9 6.7 17 264.2 4.3 18 355.8 5.2 19 256.1 4.2 0 250.3 ?1 194.3 4.1 Z2 202.0 3.7 3 148.2 24 127.3 25 99.8 4.4 26 26.9 11.0 27 235.5 10.5 28 60.7 8.2 29 32.4 11.9 30 158.2 5.7 31 168.4 4.2 1 439.2 6.2 2 213.0 3.3 3 511.4 7.2 4 173.6 2.9 5 349.2 5.2 6 197.1 7 41.7 5.8 8 554.9 7.8 9 180.2 10 181.0 4.3 11 286.5 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -72- 597.5 7.9 504.6 8.6 271.7 4.6 254.8 4.1 170.8 3.5 257.7 4.2 168.0 3.5 258.7 4.3 74.8 5.1 462.4 7.0 63.0 6.7 345.9 5.1 58.2 7.5 180.9 3.6 176.9 4.1 31.4 12.8 110.1 5.5 42.0 12.0 330.5 5.1 75.1 7.6 398.4 6.0 84.4 3.4 214.1 3.8 281.3 4.0 391.5 5.4 70.5 3.8 230.2 3.1 735.3 11.0 543.4 7.9 368.7 5.6 224.0 6.7 136.9 3.5 250.9 3.9 179.6 3.4 269.8 4.1 410.8 5.9 351.5 5.1 210.1 3.7 I17.6 8.4 290.3 4.3 53.1 7.6 302.4 4.3 80.9 6.4 176.2 3.8 126.7 4.0 68.8 7.0 1105.4 5.8 0163.6 4.6 )89.1 6.3 227.6 4.7 147.8 3.0 549.0 8.4 134.3 3.1 268.7 4.0 367.0 4.7 464.1 6.6 226.9 3.9 237.1 4.4 257.6 3.6 )153.1 11.0 1 565.6 8.2 2 63.5 6.1 3 604.5 7.9 4 266.1 4.0 112.3 3.9 6 156.2 3.4 7 339.1 4.9 8 221.2 3.9 9 343.1 4.8 0 98.3 4.5 1 208.8 3.5 2 145.5 5.2 8 23 8 24 8 25 8 26 8 27 8 28 8 29 8 30 8 31 9 1 9 2 9 3 9 4 9 5 9 6 9 7 9 8 9 9 9 10 9 11 9 12 9 13 9 14 9 15 9 16 9 17 9 18 9 19 9 20 9 21 9 22 9 23 9 24 9 25 9 26 9 27 9 28 9 2S 9 3Y 9 31 10 10 10 10 10 10 10 10 10 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 P 10 1 I10 10 10 10 10 10 10 010 )10 10 10 S10 65.0 6 112.9 1 89.8 4 255.25 166.3 385.4 173.9 20.3 9 160.2 476.4 8 598.5 9 512.8 7 238.3 3 163.5 3 300.5 4 118.0 4 697.9 8 457.4 5 222.4 611.5 226.0 398.8 452.9 190.2 284.0 367.7 235.2 174.2 85.7 52.2 173.1 122.3 I90.1 86.9 291.6 111.5 67.3 1 54.3 113.8 I133.2 1 346.5 1343.2 3453.2 1 389.8 5 215.5 6 625.9 7 191.7 8 363.6 9 288.6 0 166.3 1 226.0 2 439.5 3 273.4 4 295.8 5 162.2 .6 262.2 [7 184.4 18 75.8 19 194.3 10 105.0 Z1 353.5 22 100.4 23 62.2 24 328.4 25 114.7 26 392.7 27 262.0 28 171.3 29 299.6 30 67.0 31 140.2 1 114.2 .0 1.9 .8 5.8 5.0 i.5 .5 1.2 .8 .7 1 .5 .2 .8 .9 6.4 8.0 3.9 6.0 6.9 3.4 4.2 5.1 4.0 3.4 1.9 1.5 4.2 3.7 5.2 1.6 8.4 5.2 0.5 8.8 4.4 5.3 7.9 5.5 6.3 6.3 4.2 10.9 4.0 5.2 6.1 3.2 5.2 6.6 4.3 4.5 3.2 4.6 3.4 4.1 3.6 5.2 5.0 4.6 6.5 5.2 3.8 7.9 5.1 4.0 4.9 8.4 5.1 3.5 196.9 4.9 16.6 7.9 359.7 5.0 337.2 5.2 370.7 5.1 306.4 4.2 295.9 7.1 144.3 3.4 451.5 5.9 339.1 5.5 420.4 5.4 186.3 3.7 152.6 3.7 258.0 4.8 256.1 4.0 63.9 4.6 324.8 5.6 55.7 5.8 300.4 4.5 264.0 4.4 120.9 3.7 80.7 5.2 41.5 9.1 200.0 4.1 16.4 8.3 98.0 5.4 183.5 3.9 P179.9 4.9 60.7 9.8 478.4 8.2 239.5 4.2 213.2 4.0 422.7 6.5 184.5 3.1 386.4 4.9 287.6 6.6 124.1 4.3 491.0 6.5 575.1 9.3 561.6 9.2 1429.8 7.0 154.6 3.5 t 254.2 4.1 5 179.8 3.2 5 244.3 3.9 7 162.8 3.8 9 127.2 3.4 239.1 4.6 D 334.2 4.7 1 113.1 3.8 2 264.0 4.2 3 99.8 4.5 4 90.6 4.3 5 47.4 16.4 6 80.0 5.8 7 165.6 3.7 8 26.4 11.6 9 83.8 7.6 0 56.5 11.0 1 279.5 4.3 Z 455.4 7.1 3 197.1 3.2 1 25.6 9.3 5 455.5 9.9 5 576.5 18.7 7 492.9 6.2 8 268.1 4.1 9 344.7 5.5 0 268.1 4.3 1 207.2 3.7 [2 240.5 4.0 3 188.8 3.4 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 30 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 i 3 i 4 i5 i 6 i 7 5 8 5 9 5- 1( 5 1* 5 1: 5 1~ 5 1~ 5 1; 5 II 5 1* 5 1 5 1 5 2 5 2 5 2 5 2 5 2 5 2 5 2 5 2 .357.2 339.9 248.4 147.8 51.0 6 119.7 117.1 139.1 80.2 5 105.3 285.4 254.8 1 91.2 6 175.1 179.5 151.0 272.5 1' 251.11 290.39 342.64 95.7 4 158.0 3 324.3 z 117.7 3 71.0z 74.8z 187.5 517.2 453.3 506.7 390.0 225.3 269.2 207.3 133.0 145.2 88.2 13.7 162.8 237.3 130.7 112.1 261.5 233.4 I73.9 100.3 494.3 407.9 306.0 139.3 101.3 265.6 107.9 791.8 )269.1 1 310.4 2 203.7 3 499.7 4 99.6 5 26.9 6 186.2 7 245.8 8 33.0 9 26.0 0 458.2 1 205.2 2 70.1 3 71.3 4 263.0 5 179.5 ,6 160.6 .7 223.6 53 1.7 3.8 3.4 .9 3.6 3.4 .7 3.8 4.1 0.3 .4 4.1 0.3 1.3 1.7 .0 1.1 .8 .7 1.7 1.2 3.2 6.4 7.1 5.9 3.7 4.3 3.6 3.2 5.2 6.8 4.6 6.3 4.7 4.3 9.2 3.8 7.1 6.2 4.2 3.1 3.9 3.8 11.5 4.9 3.6 6.8 4.2 9.1 3.2 3.7 9.7 9.8 6.4 3.7 5.3 3.9 3.9 4.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 28 99.6 5.1 29 136.3 4.9 1 549.8 7.5 2 432.4 8.4 3 199.9 3.2 4 397.8 6.2 236.0 3.5 6 75.3 4.7 7 188.3 3.4 8 184.9 3.2 9 237.5 3.9 521.6 7.5 11 161.4 3.3 12 170.4 2.9 13 129.0 3.0.

14 371.4 5.4 158.5 3.4 16 142.5 2.9 17 94.9 3.5 18 104.0 3.4 19 191.0 3.3 90.5 5.2 21 53.5 8.1 22 70.0 5.6 23 187.7 3.8 24 151.0 5.3 164.3 4.3 26 184.8 4.5 27 199.7 3.8 28 60.9 9.0 29 175.0 5.3 1 453.3 6.7 2 78.5 3.9 3 412.0 6.7 4 129.2 3.1 390.2 5.9 6 344.8 5.2 7 276.4 4.2 8 275.9 3.9 9 108.1 3.3 302.2 4.4 11 153.3 3.1 12 528.3 8.8 13 115.4 4.2 14 31.2 9.0 171.6 3.1 16 312.9 4.4 17 440.9 6.6 18 119.6 4.1 19 454.1 6.3 23.2 9.4 21 295.0 4.2 22 130.0 3.8 23 233.7 5.9 24 75.8 6.2 54.1 8.3 26 98.0 6.1 27 188.1 3.9 28 225.8 4.1 29 163.1 5.1 11 235.7 5.3 12 105.8 6.0 3 89.7 3.8 14 31.5 9.9 231.2 3.7 36 164.0 2.9 7 213.0 3.8 38 144.4 3.0 3 9 449.9 7.2 3 10 391.5 5.8 3 11 109.6 3.8 9 12 142.0 3.6 -9 1; -9 1 -9 1: -9 1: -9 1.

-9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 1 -9 -9 1 -9 1 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 .9 '9 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 2( 2( 2( 21 24 2' 2' 2 2 13 180.9 14 316.6 15 87.1 6 16 153.7 17 148.0 18 83.8 4 19 130.2 20 411.0 21 170.8 22 181.9 23 146.01 24 185.7 25 66.5 26 116.5 27 139.5 28 162.2 1 208.6 2 122.1 3 52.9 6 4 337.9 5 352.2 6 393.7 7 238.1 8 406.4 9 263.8 10 120.2 11 14.5 12 151.9 13 137.9 14 153.1- 15 25.8 16 403.4 17 231.8 18 247.8 19 245.4 20 124.9 21 116.4 22 184.7 23 212.5 24 116.7 25 61.3 26 195.0 27 125.8 28 24.9 1 280.4 2 212.6 3 104.4 4 258.9 P5 204.1 I6 176.1 47 111.1 48 345.9 I9 52.9 I10 240.3 I11 385.3 I12 516.1 113 353.8 14 171.7 15 185.2 16 120.9 )17 138.1 18 116.3 19 251.2 0 20 91.1 0 21 257.0 0 22 51.9 0 23 175.2 0 24 246.7 0 25 208.4 0 26 181.5 0 27 114.7 1 1 198.8 3.7 5.2 3.0 3.5 3.4 5.8 3.5 4.2 14.9 3.8 1.5 4.3 5.2 4.1 1.7 7.4 .3 5.4 4.6 5.4 5.3 5.1 3.3 3.2 7.0 3.2 3.7 2.9 9.7 5.6 3.7 3.8 3.8 3.4 4.0 6.3 3.9 3.9 6.8 3.9 6.2 11.2 5.2 3.4 3.7 3.7 3.4 2.8 3.0 6.0 4.8 3.7 5.9 8.1 5.2 3.1 3.3 3.3 2.9 3.2 3.7 4.4 4.1 11.8 3.8 4.1 4.0 3.8 4.5 3.5 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 21 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 22 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 23 -9 2: -9 2: -9 23 -9 2: -9 2 -9 2 -9 2 -9 2 2 201.1 3 3 326.3 7 4 234.9 3 5 168.4 3 6 144.6 2 7 304.3 4 8 144.4 3 9 98.1 2 10 139.8 12 310.9 13 155.3 14 245.7 15 139.1 16 151.6 17 203.9 18 319.0 19 247.7 21 200.5 22 112.4 23 90.8 24 194.3 25 210.1 26 105.5 27 26.1 1 1 478.2 2 102.6 3 162.3 4 419.2 5 258.6 6 376.3 7 182.2 8 35.27 9 220.0 10 81.3 11 131.3 12 159.8 13 195.1 14 190.8 15 96.6 16 183.0 17 201.0 18 229.1 19 52.6 20 140.1 21 18.1 22 136.5 23 150.5 24 127.4 25 103.9 26 110.0 1 157.1 2 243.5 3 95.9 4 285.2 5 234.7 6 238.1 7 323.3 8 348.9 9 36.7 10 138.5 11 190.9 12 93.7 113 332.1 114 86.9 115 204.0 116 29.2 117 361.8 3 18 118.1 3 19 201.5 3 20 125.8 3 21 188.0 3 22 141.9 .2 '.3 1.5 .3 .2 1.5 .9 2.7 4.9 3.0 3.5 3.2 3.1 3.1 4.5 3.9 6.6 4.8 4.6 3.8 3.8 4.2 1.5 9.6 5.4 3.6 7.5 3.5 5.5 3.1 '.9 3.1 3.6 3.1 3.1 3.2 3.2 3.2 3.3 3.3 3.5 6.8 8.5 8.6 3.9 3.5 3.6 4.5 5.4 4.8 4.7 3.4 7.6 4.1 3.3 4.7 5.6 6.7 2.8 3.0 3.1 5.9 4.4 3.0 9.6 5.0 3.7 3.6 4.3 3.5 3.9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 -9 23 2- 23 2e 23 2! 23 2( 24 1 24 2 24 3 24 4 24 5 24 6 24 7 24 8 24 9 24 14 24 1 24 1: 24 1: 24 1.

24 1 24 1.

24 1 24 1 24 1 24 2 24 2 24 2 24 2 24 2 24 2 25 25 25 25 25 25 25 25 25 25 1 25 1 25 1 25 1 25 1 251 251 25 25 25 25 25 25 25 25 26 26 P26 P26 I26 26 26 26 26 26 26 9 26 9 26 9 26 9 26 9 26 9 26 9 26 9 26 0 2 3 4 5 6 7 8 9 0 2 3 5 3 5 6 7 8 9 2 2 2 190.9 152.9 151.5 144.9 255.4 41 154.1 3 419.8 7; 254.5 3 274.9 3 205.83 150.1 2 74.6 3 35.4 7 383.2 54.2 60.5 122.7 71.2 270.7 151.7 48.8 134.7 245.6 131.0 251.3 149.2 113.0 32.3 1 266.7 30.1 9 250.2 60.6 7 208.8 141.6 132.2 102.5 120.8 279.2 143.5 1 241.5 Z 215.1 3 97.0 4 141.3 5 265.7 6 363.1 7 98.0 8 196.6 9 298.7 0 99.5 1 48.9 2 98.6 3 20.3 4 96.5 1190.1 194.9 3205.3 t 165.0 5 220.9 6 120.1 7 123.3 8 88.1 9 391.9 0 70.1 1 152.1 2 139.6 .3 177.5 4 252.4 15 229.5 16 178.0 17 214.9 18 132.3 19 113.7 3.6 5.8 4.8 '.6 1.8 1.8 1.1 1.7 .7 .4 5.6 1.8 3.1 4.1 3.1 6.8 3.6 5.9 3.6 3.9 3.4 0.4 4.7 P.0 4.3 '.8 3.9 2.9 4.2 2.6 3.9 2.6 3.6 3.3 2.8 4.1 5.6 6.9 4.6 3.8 10.2 9.3 3.6 4.3 3.4 6.8 3.1 2.4 2.6 4.6 5.7 4.8 2.7 2.8 3.1 7.1 3.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 154.5 3.4 188.0 3.4 24.9 9.8 61.9 11.1 140.8 3.8 77.8 2.6 101.6 5.0 179.7 4.4 54.5 5.6 133.8 3.3 89.3 3.0 105.0 3.0 45.2 5.1 184.9 3.4 29.0 8.3 94.6 3.5 88.3 3.6 111.4 3.3 27.5 9.2 195-.7 3.9 143.7 6.7 191.1 3.4 138.4 3.3 91.7 4.6 306.5 4.6 48.8 7.3 194.1 3.7 81.2 5.8 220.8 4.8 245.9 4.8 184.4 4.3 263.9 5.6 219.1 3.9 226.0 3.2 38.8 7.7 111.1 2.7 160.5 3.1 79.4 3.3 52.5 7.5 145.8 3.0 1102.6 3.4 1203.7 5.5 i129.8 3.3 1183.1 3.8 34.9 9.1 22.1 9.5 137.6 3.4 1 74.8 5.4 Z75.1 6.2 115.2 4.6 103.3 4.6 211.0 4.6 183.6 4.4 161.3 3.2 66.7 3.7 249.9 3.8 61.5 4.3 17.6 7.9 D 41.5 8.4 1 113.3 2.7 2 124.1 3.7 3 207.0 6.6 4 106.5 4.2 111.5 3.5 6 168.9 3.3 7 163.9 3.4 8 89.1 4.9 9 27.8 9.3 0 202.0 3.3 1 144.3 3.3 1 31.9 7.6 Z 188.1 4.1 37.6 11.8 153.7 3.5 90.4 7.9 73.7 3.8 113.4 2.6 227.0 3.3 18.7 8.1 93.3 3.6 186.4 7.5 80.0 6.1 66.1 4.8 150.1 3.3 128.1 3.3 33.0 10.2 59.6 6.8 130.9 3.4 132.6 3.8 195.8 4.5 21.2 9.6 87.4 5.4 102.3 4.7 271.9 4.9 20.6 10.2 159.6 3.5 13.4 6.6 203.4 3.7 199.9 8.4 44.6 11.6 35.8 7.9 128.4 3.2 244.9 4.4 92.7 3.8 124.2 3.2 211.0 3.6 110.3 4.1 106.4 5.1 137.1 3.5 317.6 6.8 15.2 7.6 22.8 10.4 33.7 12.6 162.8 5.6 242.8 5.6 181.5 6.9 188.3 2.9 71.2 4.4 142.8 3.3 1 122.5 3.6 !183.4 3.3 ;147.5 3.5 t136.8 3.0 5 224.0 4.2 S 13.7 6.7 7 238.4 4.9 3 121.2 3.5 130.7 8.7 108.7 5.9 122.8 11.2 54.2 10.2 16.4 8.3 136.8 3.2 25.9 8.4 1 133.9 2.7 )146.0 3.2 0 98.9 3.2 1 131.4 3.0 2 52.9 6.4 3 295.5 4.6 4 78.7 4.6 5 70.6 5.2 6 21.8 9.1 7 96.0 8.9 30.3 11.4 65.2 7.1 217.8 5.2 192.9 6.7 156.3 4.5 185.0 6.4 97.7 4.1 116.7 2.8 83 .4 3.6 178.3 3. 1 184.2 3.3 10 1.9 3.6 161.4 3.6 17.4 8.5 19.3 8.4 68.2 6.4 45.2 10.2 121.1 4.6 36.0 13.2 66.8 7.7 125.0 6.8 45.8 10.6 95.9 4.2 135.5 3.3 58.3 5.2 99.9 3.6 75.5 5.0 61.5 5.7 14.4 7.2 87.6 4.3 70.5 6.1 185.1 5.1 88.3 6.2 229.9 4.9 96.3 5.5 105.5 3.3 138.9 4.1 97.8 3.6 81.8 3.6 253.7 3.8 165.3 3.2 192.4 3.9 166.2 5.0 95.4 5.9 90.1 5.7 44.8 10.3 134.5 4.3 87.7 5.5 244.3 14.2 94.3 3.8 38.6 7.0 75.6 4.6 52.3 8.2 129.5 4.1 183.5 4.5 34.1 11.9 135.6 4.2 106.3 5.1 102.5 4.8 1102.5 6.5 40.1 14.4 546.2 11.9 110.6 5.8 296.6 5.5 484.5 8.8 492.6 9.1 161.8 4.0 1075.9 20.9 24.4 13.5 1 385.0 7.2 Z 61.4 15.5 3 479.0 9.2 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 :1 2 3.1 4.1 t 19 2H 2 1~ 2 1' 2 21 2 2 2 2 682.3 1 457.4 1 350.6 383.1 107.5 126.5 393.8 99.2 6 50.5 1 334.2 12.4 9 199.9 311.3 421.6 225.6 1 31.0 1 94.5 1 94.9 1 103.3 248.4 413.9 457.2 245.8 513.6 955.6 1 417.9 1 322.8 28 1.5 265.5 72.3 4 335.8 259.2 518.8 197.6 391.5 185.0 155.6 123.4 317.7 241.9 131.0 159.6 168.6 186.9 166.7 170.9 62.0 .183.5 28.5 71.9 277.2 249.9 762.7 474.8 481.4 291.9 350.0 267.7 266.6 413.1 1 483.8 Z 537.6 3 631.6 1 642.4 5 729.0 6 158.3 7 248.4 8 211.3 9 105.6 0 199.7 1 323.7 2 220.2 2.9 0.3 8.3 7.7 4.7 8.3 1.3 5.2 8.1 9.3 16.7 5.9 1.1 9.2 5.1 5.9 3.4 7.1 2.3 4.6 3.9 3.9 6.4 4.9 7.1 8.1 4.3 5.7 3.8 3.4 3.7 4.7 3.9 4.9 3.4 7.8 4.6 13.2 10.4 5.7 3.9 9.4 6.4 6.3 4.3 5.4 4.3 5.4 6.7 7.4 9.4 11.7 3.7 4.2 3.7 5.8 4.2 3.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 101.4 5.8 301.7 4.7 192.7 3.6 26.6 10.8 18.5 8.7 157.5 5.0 72.8 6.9 207.3 4.6 132.8 6.6 81.8 7.8 252.3 5.2 348.7 5.1 570.9 7.2 206.9 3.2 84.1 3 400.9 8.5 170.0 3.0 563.1 8.6 235.1 3.5 385.8 5.2 596.9 7.8 189.1 6.2 243.9 4.4 313.0 5.2 130.8 4.1 747.1 9.9 323.1 5.4 191.9 3.7 57.3 8.3 135.8 3.6 115.0 3.9 182.2 3.6 135.9 3.6 214.2 3.7 65.2 7.7 214.4 3.7 102.1 5.0 233.0 5.0 77.3 6.4 175.6 5.6 240.2 4.6 138.7 5.7 158.1 3.4 363.3 4.9 359.6 5.1 376.3 5.5 763.2 10.2 97' 17 3.4 323.4 4.5 223.2 3.6 160.4 3.3 259.3 3.9 1 290.9 4.8 !224.7 3.9 3 72.1 5.5 t 245.6 4.2 5489.6 7.7 289.8 4.4 7 256.8 4.6 9 168.4 3.9 263.2 3.8 D 136.6 3.5 1 244.4 3.8 2 381.0 4.8 3 39.4 10.4 4 417.8 6.1 201.7 3.8 6 96.2 6.4 7 76.5 6.1 8 107.9 6.8 9 126.8 4.6 0 113.7 6.0 31 224.7 5.5 32 224.2 4.3 1 536.6 10.3 2 101.8 2.5 3 799.5 11.0 4 187.8 3.0 5 278.2 3.7 6 428.0 5.7 7 576.4 6.5 8 226.3 3.6 9 246.8 3.6 10 476.3 7.2 11 263.4 3.9 12 103.0 4.7 13 449.0 6.8 14 639.5 9.8 15 386.8 6.2 16 480.0 7.1 17 239.3 4.0 18 270.3 5.2 19 211.9 3.7 20 447.6 7.1 21 210.2 3.6 22 232.7 3.8 23 315.4 4.8 24 236.2 3.8 25 21.2 9.6 26 137.4 4.4 27 124.9 4.9 28 84.7 8.5 29 173.9 5.1 30 255.6 4.5 31 232.7 5.2 32 123.0 5.8 1 421.4 5.7 2 441.8 6.1 3 145.0 2.6 4 453.9 5.9 5 171.2 2.8 6 228.2 3.6 7 408.2 5.3 8 736.3 9.0 9 149.8 2.7 10 463.3 6.2 11 168.4 4.0 12 283.9 4.1 13 315.4 6.6 14 402.6 6.6 15 50.3 8.1 16 509.4 7.6 i17 308.4 4.6 5 18 158.3 3.3 i19 113.5 4.3 i 20 282.4 4.2 5 21 97.4 4.3 5 22 214.9 3.6 5 23 210.3 3.7 5 24 320.1 4.9 5 25 268.1 4.2 5 26 116.7 4.5 5 27 103.0 12.5 5 28 249.1 4.6 6 29 285.8 4.7 6 30 35.0 12.5 6 31 298.9 4.8 6 32 104.9 6.1 7 1 356.5 5.3 7 2 424.5 5.4 7 3 775.0 10.1 7 4 165.9 2.8 7 5 212.9 3.4 7 6 376.4 5.2 -8 -8 1 -8 -1 -8 1 -8 1 -8 -8 -8 -8 -8 -8 -8 -8 -8 -82 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 48 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 -8 7 215.4 3.4 8 413.1 5.0 9 135.2 2.8 10 469.4 5.7 11 796.8 11.3 12 168.7 3.7 13 251.9 4.8 14 282.4 4.3 15 195.1 3.7 16 162.8 3.7 17 377.8 5.2 18 128.1 3.9 19 286.0 4.5 20 257.6 4.1 21 143.6 3.5 22 164.8 3.4 23 117.7 4.0 24 186.2 3.5 25 195.3 3.9 26 149.8 4.1 27 253.8 6.0 28 146.9 3.9 29 244.1 4.4 30 280.5 4.8 31 89.7 6.8 32 127.6 5.1 1 243.1 5.2 2 121.3 2.5 3 484.5 6.0 4 516.3 7.5 5 331.8 5.4 6 495.0 7.0 7 300.1 4.4 8 520.0 7.5 9 313.5 4.5 10 95.8 5.0 11 879.7 12.7 12 756.3 11.0 13 337.3 4.6 14 291.5 4.5 15 183.0 3.3 16 142.6 3.6 17 228.9 3.5 18 194.7 3.6 19 363.2 5.4 20 222.5 4.0 21 256.3 3.8 22 338.5 4.8 23 226.3 3.9 *24 222.2 3.9 25 18.9 8.9 26 99.9 4.4 27 247.0 10.0 128 104.1 4.6 129 193.7 4.0 130 198.8 4.2 1 31 109.9 6.4 1 32 166.4 6.2 )1 314.4 6.1 )2 310.4 4.6 )3 330.2 5.5 4 541.8 6.6 5 165.0 3.1 6 284.2 3.8 7 412.1 5.1 8 494.6 7.2 99 679.2 10.1 9 10 466.2 6.5 9 11 171.3 3.3 9 12 518.1 8.0 9 13 270.3 4.2 9 14 411.0 6.4 15 16 '7 18 19 20 21 22 23 24 25 26 27 28 29 30 31 2 3 4 5 6 7 8 9 10 I12 13 14 I15 1 17 20 21 22 )23 )2~ )2( )21 32' 3 3 1 1 2 1 3 1 4 125 116 117 152.3 3 154.9 3 187.7 3 305.5 4 71.3 5.

137.5 3 78.5 4, 215.7 2 131.7 2 178.6 2 81.0 5 190.3 3 232.2 1 288.4 4 105.1- f 104.9 95.1 7 468.1 729.3 1 357.3 63.6 3 692.7 155.7 463.0 96.1 3 574.9 198.7 206.5 510.4 291.0 291.5 154.3 190.9 120.2 100.4 P143.2 I102.5 134.5 345.3 1104.9 I154.8 92.4 5 215.4 7 32.7 8 24.1 9 318.5 0 246.0 1 263.5 620.8 313.2 358.2 342.9 482.6 493.8 676.2 183.5 324.3 0 425.6 1 479.2 2 905.4 3 413.3 4 258.3 5 240.1 6 181.6 7 147.3 8 104.4 .9 181.7 ~0 365.4 1 112.3 12 365.9 13 54.5 Z4 107.1 .6 .4 .6 .6 .9 4 .4 7 .4 .6 .1 .6 .7 5.1 5.6 .8 1.4 .4 ).9 .7 6.2 .8 .0 4.7 3.2 4.3 3.9 4.1 3.2 5.8 3.2 4.9 3.8 4.1 4.1 12.8 1.

.0 4.4 42.8 10.6 4.1 4.7 8.9 5.9 4.4 7.4 7.6 12.1 6.3 4.1 3.4 3.4 6.8 3.4 5.6 4.1 5.7 8.2 3.8 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -76- -8 11 25 162.1 .3.4 -8 14 5 129.6 3.5 -8 16 18 112.9 3.2 -8 19 3 229.6 3.9 -8 11 26 259.6 5.1 -8 14 6 384.8 5.2 -8 16 19 331.3 4.6 -8 19 4 259.3 3.6 -8 11 27 199.8 4.4 -8 14 7 255.3 4.9 -8 16 20 300.0 4.2 -8 19 5 100.2 3.4 -8 11 28 118.3 5.7 -8 14 8 138.9 7.9 -8 16 21 310.2 4.2 -8 19 6 150.7 2.9 -8 11 29 217.3 4.8 -8 14 9 147.2 2.9 -8 16 22 143.0 3.5 -8 19 7 499.5 -8 11 30 125.5 5.3 -8 14 10 452.9 7.5 -8 16 23 148.8 3.6 -8 19 8 462.5 5.6 -8 11 31 134.4 5.2 -8 14 11 267.5 4.4 -8 16 24 131.3 3.8 -8 19 9 370.2 5.1 -8 12 1 402.7 6.6 -8 14 12 368.6 5.7 -8 16 25 51.5 10.7 -8 19 10 260.8 3.9 -8 12 2 922.2 17.4 -8 14 13 114.7 3.7 -8 16 26 178.8 4.0 -8 19 11 54.8 4.9 -8 12 3 189.1 2.9 -8 14 14 406.6 6.3 -8 16 27 140.7 4.1 -8 19 12 302.3 4.8 -8 12 4 389.9 5.3 -8 14 15 375.6 5.5 -8 16 28 96.0 5.5 -8 19 13 362.5 4.9 -8 12 5 371.8 5.0 -8 14 16 294.2 4.4 -8 16 29 156.7 4.5 -8 19 14 412.2 5.6 -8 12 6 308.5 4.3 -8 14 17 273.4 4.1 -8 16 30 117.4 6.0 -8 19 15 179.6 -8 12 7 274.8 4.4 -8 14 18 274.7 4.4 -8 17 1 198.8 3.8 -8 19 16 270.1 4.2 -8 12 8 20.7 8.6 -8 14 19 275.4 4.4 -8 17 2 305.1 5.3 -8 19 17 446.8 6.2 -8 12 9 325.9 5.0 -8 14 20 189.3 3.5 -8 17 3 233.8 4.3 -8 19 18 134.5 3.2 -8 12 10 527.5 7.7 -8 14 21 123.9 4.0 -8 17 4 227.2 3.6 -8 19 19 306.5 4.6 -8 12 11 273.4 3.8 -8 14 22 232.4 3.5 -8 17 5 113.2 3.3 -8 19 20 156.8 3.3 -8 12 12 369.3 6.1 -8 14 23 77.9 4.4 -8 17 6 527.3 6.6 -8 19 21 261.4 3.7 -8 12 13 91.5 5.2 -8 14 24 243.9 3.9 -8 17 7 409.8 5.7 -8 19 22 58.1 6.3 -8 12 14 194.9 3.4 -8 14 25 179.5 4.4 -8 17 8 185.7 3.3 -8 19 23 324.2 6.8 -8 12 15 415.5 5.3 -8 14 26 193.9 3.9 -8 17 9 430.6 6.2 -8 19 24 127.5 4.2 -8 12 16 377.5 5.3 -8 14 27 87.6 5.4 -8 17 10 404.6 5.9 -8 19 25 51.3 7.9 -8 12 17 209.8 3.4 -8 14 28 150.0 4.6 -8 17 11 161.0 3.2 -8 19 26 87.6 5.1 -8 12 18 332.2 4.7 -8 14 29 44.3 14.4 -8 17 12 170.5 3.1 -8 19 27 186.6 4.3 -8 12 19 198.1 3.8 -8 14 30 97.8 6.7 -8 17 13 431.8 6.5 -8 19 28 206.7 -8 12 20 281.9 4.5 -8 15 1 272.3 4.0 -8 17 14 348.8 4.9 -8 20 1 197.8 3.4 -8 12 21 154.9 3.4 -8 15 2 104.7 3.8 -8 17 15 184.7 3.1 -8 20 2 153.0 4. 3 -8 12 22 87.2 4.0 -8 15 3 715.6 9.8 -8 17 16 239.3 4.5 -8 20 3 220.0 3.9 -8 12 23 285.9 4.2 -8 15 4 384.4 6.0 -8 17 17 38.3 7.8 -8 20 4 202.1 -8 12 24 185.3 3.6 -8 15 5 239.8 4.2 -8 17 18 99.6 3.5 -8 20 5 184.9 -8 12 25 83.0 5.9 -8 15 6 715.7 22.7 -8 17 19 126.0 3.7 -8 20 6 204.3 12 26 290.8 6.8 -8 15 7 565.0 8.5 -8 17 20 322.2 4.8 -8 20 7 313.2 4.4 -8 12 27 274.9 4.8 -8 15 8 291.7 4.4 -8 17 21 116.8 3.4 -8 20 8 209.1 3.6 -8 12 28 91.4 5.8 -8 15 9 150.7 3.0 -8 17 22 286.7 4.3 -8 20 9 178.3 2.9 -8 12 29 148.6 4.2 -8 15 10 459.2 6.2 -8 17 23 315.1 4.7 -8 20 10 467.1 6.6 -8 12 30 189.0 4.2 -8 15 11 290.1 4.1 -8 17 24 215.2 8.1 -8 20 11 334.4 4.6 -8 12 31 36.2 12.2 -8 15 12 151.1 3.2 17 25 311.0 4.9 -8 20 12 295.4 4.1 -8 13 1 533.0 8.9 -8 15 13 245.4 4.1 -8 17 26 118.2 4.7 -8 20 13 268.6 -8 13 2 205.4 3.6 -8 15 14 227.4 3.7 -8 17 27 189.9 4.5 -8 20 14 293.9 4.3 -8 13 3 251.9 3.5 -8 15 15 548.5 7.5 -8 17 28 286.4 4.7 -8 20 15 49.4 9.7 -8 13 4 534.7 7.8 -8 15 16 16.8 7.8 -8 17 29 150.5 4.9 -8 20 16 94.3 -8 13 5 563.4 8.7 -8 15 17 184.3 3.2 -8 18 1 108.3 5.5 -8 20 17 130.9 3.1 -8 13 6 592.3 8.0 -8 15 18 366.1 5.0 -8 18 2 260.0 5.0 -8 20 18 21.7 8.7 -8 13 7 324.5 5.4 -8 15 19 156.1 3.1 -8 18 3 177.3 3.0 -8 20 19 96.3 3.7 -8 13 8 568.2 7.5 -8 15 20 172.7 3.2 -8 18 4 259.4 4.0 -8 20 20 112.0 3.4 -8 13 9 205.5 7.2 -8 15 21 70.7 5.3 -8 18 5 514.4 7.8 -8 20 21 267.9 4.3 -8 13 10 327.1 4.2 -8 15 22 279.7 4.4 -8 18 6 348.6 5.3 -8 20 22 55.0 7.6 -8 13 11 514.5 7.7 -8 15 23 26.3 11.9 -8 18 7 201.3 3.1 -8 20 23 38.8 11.6 -8 13 12 326.2 4.5 -8 15 24 290.5 4.3 -8 18 8 277.2 4.4 -8 20 24 89.7 4.2 -8 13 13 295.4 4.8 -8 15 25 163.9 7.5 -8 18 9 176.9 3.4 -8 20 25 202.7 3.9 -8 13 14 382.3 5.3 -8 15 26 78.1 5.6 -8 18 10 417.4 6.5 -8 20 26 85.8 6.9 -8 13 15 293.4 4.5 -8 15 27 93.5 6.7 -8 18 11 318.2 5.2 -8 20 27 98.7 5.2 -8 13 16 332.7 5.5 -8 15 28 202.0 4.2 -8 18 12 281.2 3.8 -8 20 28 24.4 11.2 -8 13 17 256.7 4.1 -8 15 29 80.3 7.0 -8 18 13 167.3 2.9 -8 21 1 224.5 -8 13 18 170.7 3.9 -8 15 30 60.6 9.3 -8 18 14 176.9 3.1 -8 21 2 234.7 -8 13 19 217.1 3.5 -8 16 1 164.7 5.2 -8 18 15 251.1 3.6 -8 21 3 241.5 3.8 -8 13 20 214.1 3.6 -8 16 3 487.3 10.3 -8 18 16 195.2 3.3 -8 21 4 131.2 2.6 -8 13 21 276.6 4.4 -8 16 4 624.0 11.3 -8 18 17 61.8 4.8 -8 21 5 236.2 -8 13 22 90.1 5.8 -8 16 5 337.8 5.9 -8 18 18 71.1 5.0 -8 21 6 354.4 5.4 -8 13 23 53.4 8.1 -8 16 6 425.2 7.0 -8 18 19 113.7 3.6 -8 21 7 241.3 3.3 -8 13 24 145.2 3.5 -8 16 7 200.3 3.4 -8 18 20 205.0 3.6 -8 21 8 293.8 4.4 A8 13 25 107.0 5.1 -8 16 8 134.9 3.2 -8 18 21 65.6 4.5 -8 21 9 306.9 4.3 -8 13 26 287.6 7.1 -8 16 9 514.5 8.7 -8 18 22 248.5 4.1 -8 21 10 215.2 3.4 -8 13 27 225.9 4.1 -8 16 10 44.3 5.8 -8 18 24 159.3 4.3 -8 21 11 344.3 4.9 -8 13 28 238.7 4.3 -8 16 11 333.6 5.3 -8 18 25 150.3 4.3 -8 21 12 281.1 -8 13 29 71.1 7.6 -8 16 12 104.5 3.7 -8 18 26 188.5 3.9 -8 21 13 98.1 3.1 -8 13 30 67.4 9.9 -8 16 13 273.8 3.7 -8 18 27 22.6 10.3 -8 21 14 272.5 3.9 -8 14 1 185.2 4.1 -8 16 14 73.5 3.9 -8 18 28 161.2 4.8 -8 21 15 10.8 5.4 -8 14 2 260.2 4.0 -8 16 15 473.4 6.7 -8 18 29 299.9 5.1 8 21 16 50.1 5.9 -8 14 3 136.7 4.9 -8 16 16 201.5 3.5 -8 19 1 320.3 6.0 -8 21 17 24.1 9.1 -8 14 4 359.7 4.8 -8 16 17 318.1 5.4 -8 19 2 104.1 3.7 -8 21 18 208.9 3.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -77- 19 37.9 8.8 141.8 3.7 21 28.1 11.4 22 224.1 7.8 23 20.0 9.0 24 93.8 6.6 54.0 10.7 26 131.4 4.9 27 66.0 8.4 1 275.5 7.6 2 276.7 4.7 3 184.2 3.6 4 205.2 3.5 263.9 3.5 6 545.5 6.7 7 386.6 5.6 8 210.0 3.3 9 74.6 3.9 101.3 3.3 11 202.5 4.5 12 50.5 4.8 13 96.4 3.4 14 23.5 10.3 66.9 4.4 16 65.4 4.7 17 196.5 3.6 18 76.5 3.9 19 184.0 3.7 111.3 3.4 21 98.6 11.8 22 151.6 3.7 23 26.9 10.9 24 110.8 4.5 156.1 3.7 26 108.1 4.7 27 133.7 5.1 1 187.4 4.7 2 268.9 5.5 3 73.1 8.5 4 205.9 3.3 342.7 4.6 6 347.9 4.2 7 112.6 3.0 8 141.3 3.2 9 52.5 3.8 229.3 3.7 11 76.8 4.0 12 257.8 3.7 13 107.6 3.0 14 273.8 4.3 213.9 3.4 16 53.6 5.6 17 215.8 3.4 18 62.8 4.8 19 127.5 3.2 142.5 4.0 21 16.9 8.2 22 55.9 8.1 23 115.4 3.7 24 135.2 4.0 82.5 6.4 26 68.8 7.4 1 160.0 3.0 2 511.2 8.3 3 209.3 4.6 4 176.2 4.2 141.0 2.5 6 142.6 2.5 7 125.6 2.5 8 193.2 2.9 9 61.8 3.3 320.0 5.1 24 11 24 12 24 13 24 14 24 15 24 16 24 17 24 18 24 19 24 20 24 21 24 22 24 23 24 24 24 25 24 26 25 1 1 25 2 25 3 25 4 1 25 5 25 6 25 7 25 8 25 9 25 10 25 11 25 12 25 13 25 14 25 15 25 16 25 17 25 18 25 19 25 20 25 21 25 22 25 23 25 24 25 25 26 1 26 2 26 3 26 4 26 5 26 6 26 7 26 8 26 9 26 10 26 11 26 12 26 13 26 14 26 15 26 16 26 17 26 18 26 19 26 20 26 21 26 22 26 23 26 24 26 25 27 1 27 2 27 3 27 4 27 5 27 6 225.5 100.5 144.0 61.6 232.9 162.2 212.8 38.6 227.0 73.2 218.9 117.9 92.8 228.7 161.0 125.5 133.0 ~52.1 10.3 193.2 ~01.2 136.8 ~09.4 56.0 162.8 173.1 130.5 153.8 124.8 198.8 281.9 148.4 95.6 181.2 188.2 68.8 218.2 148.2 207.9 137.2 80.1 284.1 204.5 46.3 149.4 150.1 179.0 239.5 183.0 45.4 175.4 157.5 64.8 81.4 25.3 355.2 68.1 98.9 193.5 224.0 184.4 246.7 42.6 142.6 239.8 84.6 118.7 94.2 49.4 432.4 94.4 113.0 3.2 3.0 2.8 5.5 3.4 2.9 3.4 8.5 3.6 9.9 4.2 3.9 5.1 4.0 3.7 4.4 4.0 5.1 4.6 3.4 2.9 2.8 3.0 4.9 5.0 2.8 2.8 3.4 3 4.1 2.8 4.0 3.1 9.4 7.1 3.8 3.4 3.8 4.1 6.1 5.2 4.1 12.4 2.8 2.7 2.7 3.4 2.7 5.8 2.9 2.6 3.4 4.5 8.8 5.0 5.3 3.8 7.8 3.7 3.4 4.3 10.2 3.8 4.3 5.5 4.0 4.1 4.8 7.5 2.5 2.8 48.2 5.6 139.9 2.5 182.2 2.7 137.7 2.6 209.1 3.0 110.6 3.0 128.6 3.0 64.4 4.3 235.6 3.8 160.9 3.3 370.4 9.8 207.8 3.5 18.5 8.4 78.0 5.6 51.0 6.9 124.4 3.8 127.6 4.8 33.7 12.7 82.3 5.0 236.0 4.6 269.4 5.2 91.0 3.4 66.0 4.6 117.5 2.5 132.3 2.6 141.0 2.5 56.6 4.7 59.3 3.6 64.0 4.4 52.6 4.5 149.3 3.3 208.8 3.4 194.0 3.9 141.4 8.2 49.4 7.5 93.1 5.0 308.4 4.9 134.3 3.7 225.0 3.7 115.9 3.6 56.4 5.8 158.8 3.8 67.0 5.5 98.6 5.1 105.1 3.9 172.4 3.0 231.2 4.1 185.8 2.9 116.7 2.5 206.7 3.9 224.9 3.5 152.4 2.8 75.4 4.8 48.4 6.8 32.5 12.7 100.3 7.3 182.7 3.1 187.1 3.3 1237.4 4.5 )86.0 4.9 )20.3 9.0 1 22.7 9.4 36.0 11.1 163.3 4.0 159.2 3.7 96.7 2.9 19.6 7.9 225.1 3.6 163.9 3.2 199.4 3.8 119.8 2.7 112.3 3.2 141.2 2.7 81.1 4. 1 82.7 4.1 226.7 7.9 95.0 108.6 2.9 115.0 3.4 206.5 3.6 129.9 3.7 41.3 8.6 205.8 3.6 183.4 3.4 290.7 5.7 254.3 5.2 205.5 4.2 300.0 6.9 284.4 9.1 135.6 2.9 140.5 136.9 171.7 2.8 137.9 2.9 158.8 50.9 10.8 222.0 3.3 30.4 9.6 97.0 4.3 296.4 4.7 83.9 18.8 8.8 207.7 3.7 24.9 9.6 95.1 4.4 112.6 3.8 142.5 3.7 29.6 10.4 204.4 4.4 99.0 4.1 138.2 100.6 3.2 220.2 6.2 306.0 168.2 3.1 313.4 5.2 69.5 4.8 116.3 3.4 171.0 3.3 146.9 3.2 113.0 3.8 169.6 3.6 83.9 4.7 215.5 4.6 14.3 7.2 13.4 6.8 46.0 10.3 151.3 4.7 221.2 10.8 126.3 6.9 161.9 140.6 3.2 139.6 3.3 61.2 75.8 3.7 1 81.1 3.9 4 163.4 3.2 5 90.6 3.6 5 213.7 3.1 7 63.8 7.1 R 109.6 79.6 7.2 71.2 86.2 8.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -78- 4 79.4 5.6 96.6 5.4 6 149.8 3.1 7 194.9 3.2 8 63.2 4.1 9 130.9 2.7 243.1 5.0 11 90.4 3.8 12 273.5 4.6 13 176.4 3.5 14 173.7 3.2 92.4 3.7 16 109.8 3.5 17 98.3 4.0 1 134.3 4.1 2 119.6 3.7 3 65.3 6.6 4 261.8 5.5 82.9 5.4 6 84.5 6.4 7 177.7 3.2 8 157.0 3.4 9 171.3 2.8 203.7 3.7 11 119.9 3.2 12 161.9 3.4 13 129.0 3.1 14 74.4 4.4 172.9 3.0 16 106.3 4.7 1 62.0 5.6 2 58.1 6.9 3 154.1 4.2 4 93.2 4.8 116.7 4.4 6 120.5 5.7 7 65.7 5.1 8 42.6 5.6 9 230.7 3.5 95.9 3.5 11 296.5 5.1 12 124.6 3.4 13 82.5 3.6 14 19.5 9.1 1 102.9 4.0 2 221.4 4.3 3 309.8 24.9 4 299.5 6.3 142.8 3.9 6 100.6 4.7 7 94.3 3.6 8 212.8 4.0 9 81.9 4.0 68.4 4.2 11 136.1 2.9 12 14.4 7.2 1 50.2 7.8 2 114.0 4.3 3 60.1 6.0 4 141.2 4.2 57.4 7.1 6 87.7 5.5 7 87.8 7.8 8 102.5 3.4 9 84.3 3.2 212.5 3.9 1 155.3 4.2 2 198.9 4.6 3 84.9 5.3 4 74.4 5.0 133.1 3.8 6 97.2 4.7 172.7 9.0 15.3 9.8 429.2 8.1 191.8 3.9 292.8 4.9 203.7 4.3 667.4 14.2 277.9 6.0 327.4 6.1 302.9 5.6 77.8 5.8 383.3 7.8 12.8 9.0 93.7 5.8 269.7 5.9 195.7 10.1 90.0 5.3 357.8 7.8 155.4 4.8 98.6 6.5 104.7 5.1 257.9 5.9 356.8 7.2 204.0 4.9 339.7 7.4 219.7 5.5 120.0 5.5 303.6 7.3 14.6 10.8 13.7 10.2 60.9 15.7 229.6 6.6 15.4 11.0 128.0 7.5 348.5 4.1 90.7 2.5 190.5 2.6 251.5 3.1 254.8 4.0 228.8 3.5 513.8 8.0 536.4 6.9 438.6 6.8 I187.7 3.1 140.1 2.8 162.3 2.9 1396.6 6.2 1 542.9 7.6 5495.1 7.7 i423.6 7.0 1 584.7 9.1 1308.3 4.8 18.5 9.1 36.9 10.0 1 167.2 3.4 Z 381.0 5.3 3 172.9 3.3 4 39.0 8.8 5 138.6 3.8 5 38.3 12.1 7 112.2 4.3 8 242.5 6.2 9 155.7 3.8 0 52.4 10.9 1 198.4 4.8 2 27.0 11.4 3 66.0 9.3 1 196.8 2.9 295.5 3.9 1112.3 2.4 t 221.6 3.0 5 193.2 2.8 321.3 5.1 226.7 3.7 242.3 3.3 219.6 3.2 740.6 9.8 436.5 6.4 658.4 8.9 342.8 5.4 498.2 6.9 442.2 6.4 254.4 4.3 356.0 5.7 323.0 5.0 146.4 4.4 254.6 4.4 140.6 4.9 190.0 3.7 50.1 8.0 210.0 3.7 16.3 7.9 186.5 3.5 107.3 5.0 164.8 6.6 139.9 4.1 117.6 5.8 222.4 4.9 72.9 8.9 38.6 13.0 521.3 9.9 304 .5 4.2 217.4 4.0 387.3 6.5 112.0 2.5 340.8 5.0 529.9 8.0 300.8 4.2 688.7 8.9 390.0 5.1 150.0 2.8 231.1 3.3 23.9 9.6 58.5 9.2 298.4 5.8 365.8 5.7 330.5 5.5 333.7 5.1 419.0 5.8 163.7 3.8 140.6 4.2 235.7 3.7 299.7 4.4 152.9 3.3 108.0 3.9 78.3 6.8 97.4 5.3 247.5 4.7 88.3 6.2 203.8 4.5 145.9 4.6 124.6 11.1 77.7 3.4 334.6 6.0 .275.4 4.0 470.4 8.5 626.0 8.1 340.2 5.1 101.1 3.7 417.1 7.0 663.9 8.7 D 408.8 5.2 1 338.4 5.4 2 298.9 4.0 370.1 5.2 424.6 5.8 355.9 5.9 614.3 9.7 423.3 7.1 231.0 3.9 257.4 3.9 127.3 3.9 118.4 3.9 179.7 3.6 177.0 3.4 171.4 3.4 248.5 4.1 218.3 3.7 231.4 3.9 114.0 12.6 196.1 4.1 83.5 142.8 5.1 105.0 6.1 43.0 13.1 136.5 3.6 287.9 270.3 3.7 518.9 7.7 498.1 6.9 668.1 8.8 267.0 3.3 679.4 9.2 375.1 985.9 13.7 236.5 3.7 270.6 5.6 255.6 4.1 276.6 4.1 197.5 3.8 216.1 3.8 255.9 278.8 4.4 164.9 207.4 3.9 304.4 4.8 201.8 3.6 263.1 4.2 143.7 40.3 9.3 194.5 3.7 142.0 3.6 256.9 8.3 141.2 5.2 I128.8 4.8 182.4 4.9 44.5 13.3 226.7 3.7 235.7 3.3 132.1 2.4 451.4 5.7 384.9 113.2 2.7 270.4 3.8 181.1 2.8 456.5 6.3 398.4 5.6 1 110.3 Z 378.7 5.6 3 326.4 4.6 1 362.4 5.3 5 219.7 3.7 5 657.6 9.9 7 157.6 3.4 B 331.2 4.8 9 209.3 3.7 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 227.8 4.3 211.3 3.7 190.4 3.6 85.8 7.5 299.5 4.3 130.6 3.5 132.7 4.8 220.3 4.1 311.2 11.8 68.6 8.7 43.7 14.6 145.5 5.3 22.8 11.4 646.8 11.4 329.3 4.5 481.2 6.8 338.8 5.0 216.3 3.1 515.1 7.4 526.4 8.0 264.2 3.6 222.0 3.4 143.4 2.9 350.3 4.7 411.7 6.1 586.5 8.8 518.9 7.4 279.4 4.2 324.8 5.3 171.6 3.6 226.5 3.9 24.8 10.3 214.6 3.7- 187.4 3.9 197.7 4.0 132.7 3.8 311.5 4.5 148.0 3.6 184.8 3.6 117.0 4.2 293.2 7.1 240.8 4.2 I70.5 8.3 195.0 4.7 76.5 8.7 133.6 5.7 251.3 3.8 555.8 9.8 196.1 3.0 161.6 2.6 448.6 6.5 105.1 2.9 411.2 5.6 841.2 10.3 344.4 4.3 1 381.2 5.2 Z189.9 5.6 3 426.4 5.9 1 359.4 5.4 297.2 4.8 293.5 4.7 7 334.3 5.7 9 159.6 3.5 S125.0 4.1 0 333.3 4.8 1 216.1 3.9 2 203.4 3.5 3 61.3 6.0 4 121.3 3.6 299.9 4.2 6 143.6 4.5 7 65.6 7.4 -7 E -7 E -7 E -7 E -7 -7 -7 S -7 -7 -7 Sj -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 1 -7 1 -7 1 -7 1 -7 1 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 28 29 30 31 32 2 3 4 5 6 7 8 9 10 11 12 13 15 16 17 18 19 20 2 1 22 23 24 25 26 27 28 29 30 31 32 2 '3 '4

)I

I

D02 0 2 0 2 0 2 0 2 0 2 02 0: 0: 0: 1 1 1 142.9 70.3 7 196.3 166.4 107.1 184.7 5 426.6 5 51.1 7.

562.0 7 588.0 8 356.6 4 647.5 8 437.2 7 431.1 5 115.2 373.1 518.3 300.2 438.3 502.4 203.1 97.0 6 55.7 6 252.4 258.3 323.1 98.5 96.1 122.0 89.0 92.24 15.9 333.1 191.3 59.4 202.4 218.0 493.5 811.2 538.7 832.4 396.9 607.4 1294.1 339.1 0 375.9 1 339.4 2 543.2 3 593.6 4 563.0 5 318.3 6 311.3 7 442.1 8 159.2 9 284.9 :0 364.3 1 104.5 2 350.1 ~3 113.3 4 231.2 ~5 144.4 ~6 94.6 ~7 195.1 ~8 94.2 ~9 239.8 W0 274.0 31 158.3 32 163.1 1 236.2 2 568.4 3 951.6 4 170.8 .2 .0 1.3 5.2 6.3 .8 .5 .4 .0 .6 .2 .9 2.7 5.8 7.6 5.1 6.4 7.4 3.8 i.4 3.8 4.1 5.6 1.4 1.2 4.0 t.8 6.2 7.9 5.2 4.5 6.0 3.6 6.6 11.3 7.6 10.0 5.5 9.5 3.9 5.3 5.5 4.7 8.6 8.4 9.1 4.6 4.8 6.4 3.3 5.3 5.7 4.0 5.8 3.5 3.4 4.4 4.4 6.1 5.8 4.4 6.3 4.6 4.3 4.2 7.7 13.0 2.7 290.8 4.5 528.5 7.0 453.9 5.8 319.6 4.7 227.9 3.2 D 362.5 4.5 1 231.6 3.4 2 442.5 6.2 3 155.1 3.0 4 423.6 5.7 5 85.9 4.0 6 364.6 5.6 7 152.3 3.2 8 230.7 4.0 9 106 .0 4.3 0 261 .7 4.1 1 186 .4 3.3 2 45.8 7.1 3 73.6 7.7 4 89.3 5.1 5 168.2 4.1 6 109.1 4.5 7 307.4 8.0 8 223.3 4.4 9 271.1 4.5 0 40.8 15.5 1 122.8 7.2 2 155.8 6.9 1 637.9 9.9 2 623.6 9.0 3 376.2 5.1 4 322.7 5.4 5 583.3 7.4 6 209.6 2.8 7 260.6 3.7 8 323.3 5.0 9 178.9 3.5 .0 408.5 6.0 A1 143.1 3.2 2 419.9 6.1 [3 494.8 6.7 4 429.3 6.9 15 310.7 5.2 16 409.4 6.1 17 227.2 3.9 18 196.1 4.0 19 328.2 5.0 20 60.1 5.9 21 28.4 11.2 22 179.0 4.0 23 260.4 3.9 24 121.8 3.6 25 157.8 3.8 26 72.5 5.6 28 218.1 3.9 29 188.0 4.4 30 53.3 13.6 31 149.5 5.6 1 408.1 5.9 2 151.7 2.5 3 497.8 6.6 4 359.5 4.9 5 178.5 2.9 6 391.4 5.2 7 464.6 6.2 8 429.4 5.6 9 378.3 5.6 .10 335.3 4.2 11 406.7 5.7 12 676.3 9.9 13 236.7 4.5 14 599.6 8.8 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1.

-7 1.

-7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 1 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4- 4 4 4 4 4 4 4 .4 .4 .4 4 [4 [4 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 1: 1; 1, 15 141.7 16 219.9 17 265.0 18 217.7 19 145.6 20 204.1 21 112.6 22 48.8 8 23 191.7 24 251.1 25 47.5 1~ 26 264.6 27 220.3 28 208.4 29 164.6 30 197.0 31 100.7 1 653.8 1 2 366.8 3 192.43 4 173.02 5 763.9 6 571.0 7 472.4 8 633.0 9 413.2 10 267.7 11 454.7 12 787.5 13 311.8 14 219.6 15 83.3 16 128.2 17 189.9 18 96.1 19 185.9 20 205.0 21 214.8 22 21.4 23 243.1 24 173.7 25 193.4 26 331.3 27 141.0 28 181.7 29 136.8 30 163.8 31 81.5 1 321.9 2 427.2 3 216.8 4 1119.4 5 186.8 6 356.9 57 492.1 8 31.7 5 9 280.7 5 10 293.0 5 11 167.0 5 12 259.7 5 13 542.0 5 14 144.5 5 15 141.3 5 16 514.2 5 17 151.8 5 18 66.8 5 19 223.8 5 20 140.7 5 21 55.1 5 22 63.2 5 23 71.8 5 24 132.4 3.9 3.8 4.3 3.7 3.4 3.6 3.8 .0 4.8 4.1 4.4 4.1 4.2 6.1 2.9 3.2 7.2 5.4- 4.8 11.8 3.7 4.3 3.8 3.4 4.7 3.7 8.9 3.7 3.4 4.2 7.7 4.1 4.2 5. 3 7.3 4.7 9.3 14.0 4.1 5.3 7.1 9.8 7.3 4.1 3.8 4.1 3.1 3.3 7.1 3.2 5.9 6.1 4.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 231.4 184.5 266.1 178.9 108.9 201.7 266.4 536.7 498.9 645.6 275.5 367.5 159.6 339.7 405.4 290.5 200.4 74.6 406.8 256.8 169.1 292.8 226.2 443.9 323.8 178.4 141.9 70.2 181.5 228.1 29.7 380.6 235.6 123.1 116.3 29.8 278.5 878.5 410.1 479.8 353.0 601.7 238.7 284.7 135.9 339.6 92.5 359.1 303.6 274.1 233.6 254.0 259.8 272.6 160.3 P91.2 170.0 *169.9 334.8 *219.5 198.3 209.2 289.4 241.2 106.3 133.0 405.4 232.4 483.9 583.9 787.9 835.7 .5.3 4.7 4.6 4.8 5.9 4.3 6.4 8.0 6.8 9.4 4.5 4.6 5.1 5.0 6.0 5.1 3.6 4.0 5.6 4.0 3.0 4.7 3.8 6.8 4.8 3.8 3.6 4.7 3.6 3.9 14.2 6.1 4.2 4.8 5.8 12.3 6.7 12.7 5.5 7.0 5.2 8.3 3.6 4.4 3.7 4.9 4.1 5.2 4.6 4.1 4.1 4.3 3.9 3.8 3.9 4.6 3.1 3.4 4.8 3.9 6.8 4.7 4.5 4.5 5.5 12.9 9.0 7.9 6.9 7.1 10.9 13.2 549.3 8.5 209.7 3.2 235.6 4.0 140.4 2.9 135.1 3.0 404.8 6.7 174.6 3.0 190.6 3.4 278.0 4.3 143.6 3.0 345.4 5.3 169.3 3.8 184.9 3.6 111.8 3.6 82.1 5.1 50.4 10.2 280.0 4.5 19.2 9.5 101.6 5.3 246.1 4.5 141.3 4.8 180.2 4.3 216.5 5.1 306.2 5.3 406.1 7.3 169.7 2.8 201.5 2.9 147.9 3.3 237.2 3.5 93.8 3.3 287.6 4.1 327.5 4.9 696.8 9.2 376.6 6.5 183.9 3.3 355.5 5.0 61.8 5.1 344.8 5.5 201.6 3.3 303.8 4.2 78.8 4.4 386.3 6.2 347.6 5.1 157.6 3.5 118.1 3.4 106.4 4.1 185.7 9.6 93.4 5.9 79.9 5.6 83.2 6.5 62.6 7.7 225.0 5.0 639.5 12.6 513.8 9.4 374.4 5.9 291.0 4.7 184.7 2.9 286.8 3.7 242.1 3.3 232.7 3.5 359.8 5.3 I141.7 2.8 267.5 4.0 t422.1 5.2 1302.9 4.6 I 209.1 3.2 i233.2 3.6 i234.6 4.5 7290.7 4.6 158.1 3.4 )65.5 6.8 209.3 3.6 -7 20 -7 20 -7 20 -7 20 -7 20 -7 20 -7 20 -7 20 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 21 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 22 -7 23 -7 23 -7 23 -7 23 -7 23 -7 23 -7 23 -7 23 146.3 3.8 183.8 3.4 26.2 12.5 189.9 3.7 45.3 8.4 141.4 6.1 88.5 5.6 140.1 5.3 535.8 10.1 28.8 11.1 251.7 4.5 275.2 4.0 296.8 4.2 252.4 3.9 165.9 2.8 82.6 3.4 166.2 2.9 346.8 5.2 708.5 9.9 303.8 4.4 113.8 3.4 61.1 4.9 128.0 3.0 73.2 4.0 118.7 3.3 197.1 3.4 88.3 3.4 97.9 3.9 25.4 10.2 79.4 4.9 16.4 8.3 107.2 4.4 124.8 5.6 39.4 12.5 107.6 5.7 124.6 6.6 45.0 5.7 564.8 9.9 224.4 3.4 611.9 8.2 148.9 2.7 151.2 2.6 431.3 6.0 348.1 6.0 226.3 3.4 I92.0 3.2 61.3 4.2 218.7 3.3 309.8 4.4 304.8 4.4 i46.7 5.3 225.9 3.5 34.5 8.4 159.7 3.0 151.4 3.3 105.5 3.8 170.4 3.6 303.6 6.2 1 238.6 3.8 I 187.4 3.8 i58.5 7.7 i64.0 7.5 1 38.9 12.6 1148.6 4.5 383.4 6.5 61.8 6.7 360.6 5.3 161.2 3.1 192.7 3.3 233.1 3.3 477.1 6.2 158.0 2.7 PCT/GB98/02542 7 23 9 252.6 3.6 7 23 10 291.3 4.7 7 23 11 253.4 3.4 7 23 12 228.2 3.4 7 23 13 56.9 4.6 7 23 14 215.2 3. 3 7 23 15 70.8 5.1 7 23 16 65.0 4.9 7 23 17 279.8 7 23 18 256.4 3.7 7 23 20 107.3 3.4 7 231 21 51.0 11.7 7 23 22 133.2 7 23 23 71.6 5.6 7 23 24 16.1.6 3.6 7 23 25 75.7 7 23 26 80.6 7 23 27 70.2 8.1 7 24 1 238.9 5.2 7 24 2 225.7 4.7 7 24 4 238.3 3.1.

7 24 5 47.3 3.7 7 24 6 62.9 3.9 7 24 7 113.5 7 24 8 200.5 3.2 7 24 9 25 1.3 7 24 10 57.2 7 24 11 270.5 7 24 12 226.2 3.4 7 24 13 77.3 3.6 7 24 14 146.8 2.8 7 24 15 129.9 3.6 7 24 16 177.3 3.4 7 24 17 326.0 4.6 7 24 18 146.4 3.1 7 24 19 83.2 4.2 7 24 20 85.6 4.6 7 24 21 63.5 7.2 7 24 22 210.0 3.7 7 24 23 123.8 3.8 7 24 24 125.5 5.2 7 24 25 158.7 5.3 7 24 26 31.8 11.3 7 25 1 90.2 4.4 .7 25 2 301.3 6.8 .7 25 3 158.7 3.8 ,7 25 4 215.4 4.1 .7 25 5 48.4 3.9 .7 25 6 151.6 2.6 .7 25 7 66.5 .7 25 8 276.3 4.3 .7 25 9 226.2 3.2 .7 25 10 70.0 3.3 .7 25 11 323.4 4.7 .7 25 12 120.4 2.7 .7 25 13 63.4 3.3 .7 25 14 408.6 6.1 .7 25 15 59.7 5.2 -7 25 16 231.8 3.7 .7 25 17 87.4 3.6 -7 25 18 161.5 3.1 -7 25 19 16.1 7.6 -7 25 20 178.4 9.1 -7 25 21 171.6 3.4 -7 25 22 222.1 3.8 -7 25 23 83.0 6.4 -7 25 24 93.5 4.4 -7 25 25 78.0 6.3 -7 25 26 174.2 5.8 -7 26 1 219.3 4.6 -7 26 2 102.0 4.2 -7 26 3 188.9 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 -81- 4 15.1 6.9 147.3 2.5 6 225.1 3.3 7 349.7 4.4 8 112.5 2.5 9 83.5 3.5 112.0 2.6 11 102.7 2.7 12 13.7 6.7 13 189.1 2.9 14 120.6 3.0 158.2 2.8 16 75.4 4.2 17 206.8 3.5 18 13.0 6.5 19 232.4 6.8 122.2 4.2 21 278.6 4.5 22 238.9 4.1 23 227.0 4.5 24 253.9 4.5 144.2 5.1 1 310.5 6.6 2 234.4 4.9 3 303.7 5.7 4 209.3 3.7 195.9 4.1 6 82.6 2.6 7 37.9 5.7 8 192.7 2.6 9 144.7 2.5 167.2 2.6 11 40.9 7.4 12 49.2 4.4 13 175.1 2.8 14 67.1 4.9 283.9 4.0 16 163.0 2.9 17 181.5 3.0 18 297.9 8.0 19 140.2 3.3 293.3 5.1 21 148.0 3.5 22 312.1 4.3 23 148.6 4.2 24 198.2 4.1 1 122.6 3.7 2 157.5 3.7 3 252.5 4.9 4 101.8 3.0 69.4 2.8 6 85.6 3.0 7 10.6 5.2 8 90.2 2.7 9 93.5 2.9 83.7 3.4 11 96.9 3.6 12 201.0 3.2 13 62.5 5.6 14 274.9 4.2 57.2 4.6 16 190.3 3.4 17 254.5 6.1 18 199.8 3.4 19 115.0 5.1 295.4 4.7 21 272.6 4.3 22 154.0 3.8 23 75.6 6.6 24 34.6 12.9 1 141.3 3.4 2 82.8 4.3 394.8 7.7 67.0 6.3 77.6 4.0 286.8 4.7 372.4 4.8 308.9 4.4 249.8 3.4 227.2 3.6 212.1 2.9 182.5 3.0 146.3 3.5 21.7 8.3 154.6 3.2 230.7 5.3 256.8 4.4 144.3 3.1 305.8 5.8 149.9 4.0 248.0 4.2 76.6 5.4 107.5 3.9 191.8 4.5 140.9 3.4 306.4 6.4 133.4 3.5 77.9 3.3 198.7 2.8 247.0 3.4 295.0 4.0 251.2 3.5 138.7 3.2 292.9 3.9 150.8 2.9 155.3 3.2 *244.4 4.3 *200.4 3.4 195.9 3.3 83.5 4.0 70.3 4.4 I110.8 5.7 1168.0 3.9 *72.3 6.0 238.5 5.0 243.0 4.9 214.4 4.1 220.6 4.5 200.7 3.2 53.7 3.6 84.5 2.8 107.9 2.5 25.1 8.0 )162.2 3.0 1 68.3 4.2 Z 165.4 3.1 3 154.3 7.9 1 206.1 3.2 5 237.9 3.4 5 200.9 4.1 7 141.7 3.2 8 125.5 4.0 9 60.1 6.6 0 133.4 4.4 1 141.3 3.8 120.2 3.5 147.6 3.5 1 97.6 3.7 1 156.8 4.1 5188.9 4.3 5 147.5 2.7 7 177.6 3.0 3 199.2 3.3 111.5 2.4 186.5 3.1 219.0 6.6 189.1 3.7 130.6 3.9 38.1 7.9 59.2 5.3 174.7 3.1 89.9 5.7 117.6 3.4 135.1 3.4 23.8 9.9 68.1 4.8 59.3 6.2 365.1 7.2 148.9 3.5 191.6 4.2 33.3 7.2 235.1 3.4 154.9 4.4 241.7 7.1 119.8 3.2 316.2 4.3 288.2 4.1 48.7 5.4 157.4 3.5 74.7 3.4 72.3 4.6 192.1 3.3 68.8 5.2 118.0 3.2 160.8 4.0 14.5 7.1 159.5 4.2 13.5 6.8 118.3 6.6 257.7 6.5 149.6 3.7 89.2 3.1 142.6 2.6 182.4 3.1 65.9 4.7 93.1 3.3 154.8 2.9 63.3 4.8 214.4 4.0 104.4 3.3 100.0 3.6 112.6 5.1 53.0 6.6 237.8 6.2 132.5 3.8 150.3 4.3 297.4 6.0 299.1 5.0 18.3 7.9 167.3 3.2 54.0 4.7 157.9 2.7 130.1 7.6 !65.3 3.9 ;149.6 2.9 t 133.3 2.9 5 212.4 4.1 5 67.4 4.4 7 54.9 5.9 39.3 7.6 61.1 5.9 185.0 4.3 70.4 5.2 66.7 6.0 98.8 4.4 77.1 3.6 PCT/GB98/02542 36 8 169.9 36 9 207.8 3.4 36 10 189.7 3.1 36 11 71.5 36 12 268.5 3.8 36 13 73.1 4.4 36 14 100.6 3.2 36 15 70.3 .37 1 102.8 37 2 48.3 6.2 37 3 101.0 3.6 37 4 115.3 3.9 37 5 70.8 5.7 37 6 153.0 37 7 131.9 37 8 214.8 3.8 37 9 43.5 37 10 86.5 3.1 37 11 121.5 2.8 37 12 208.4 3.4 37 13 12.8 6.3 37 14 156.9 4.7 38 1 53.0 5.4 38 2 148.2 4.7 38 3 84.7 4.3 138 4 121.0 3.6 138 5 161.9 4.6 138 6 42.8 1 38 7 107.1 2.9 1 38 8 181.5 4.3 1 38 9 172.6 2.8 7 38 10 169.8 3.1 7 38 11 225.1 7 38 12 81.8 4.8 7 39 1 325.7 5.9 7 39 2 250.8 5.6 7 39 3 165.3 3.4 7 39 4 109.9 3.6 7 39 5 70.5- 5.2 7 39 6 152.3 7 39 7 63.1 6.2 7 39 8 148.0 3.1 7 39 9 102.3 2.8 7 40 1 35.2 7 40 2 13.4 7 40 3 62.2 7 40 4 103.1 3.6 7 40 5 23.7 9.3 7 40 6 100.5 4.7 6 0 1 274.9 6 0 2 729.2 13.9 6 0 3 725.1 12.6 6 0 4 340.8 7.2 6 0 5 42.6 5.8 6 0 6 563.1 14.7 6 0 7 274.7 5.9 6 0 8 26.8 10.6 6 0 9 16.4 9.4 6 0 10 7.2 5.3 6 0 11 328.4 6.1 6 0 12 42.3 15.0 .6 0 13 79.9 5.1 .6 0 14 75.2 7.4 .6 0 15 163.2 10.6 .6 0 16 342.1 .6 0 17 90.7 7.8 -6 0 18 247.7 -6 0 19 472.7 11.3 -6 0 20 278.3 6.4 -6 0 21 59.2 9.7 -6 0 22 454.4 8.7 -6 0 23 14.2 9.9 SUBSTITUTE SHEET (RULE..26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 270.6 6.5 136.0 6.0 53.1 16.1 243.4 5.2 219.5 6.1 275.0 13.3 228.9 9.3 153.2 9.0 107.9 13.1 79.6 17.0 60.9 3.0 440.0 7.2 271.6 3.5 138.7 2.4 253.8 3.5 334.9 5.0 499.8 7.5 193.0 2.7 323.7 5.0 451.1 6.6 148.6 2.9 259.0 4.5 417.3 6.3 675.3 7.8 404.1 5.9 278.8 6.1 296.6 4.7 274.8 4.7 347.6 5.9 611.2 9.2 205.9 3.5 271.4 4.1 196.0 3.6 275.9 4.4 113.0 3.9 149.6 3.7 142.5 4.4 183.3 3.8 214.8 9.6 P115.6 6.2 218.2 4.6 24.4 12.1 84.1 12.0 226.6 3.4 428.0 6.1 327.3 4.0 409.0 6.2 37.1 4.5 421.8 7.6 272.0 4.2 383.6 5.1 583.2 9.0 I340.4 4.6 100.8 3.3 t410.3 5.1 1134.0 2.9 1 415.6 5.4 i164.9 4.4 i624.8 8.3 1 280.8 4.7 1313.5 5.5 )218.6 4.6 )127.3 4.1 1 286.7 4.4 Z 182.4 3.6 3 113.9 3.6 4 285.4 4.5 277.7 4.2 97.5 5.4 7 80.7 7.6 8 199.9 4.9 9 285.2 8.9 30 135.3 6.3 31 85.2 10.2 32 175.4 6.2 33 107.8 8.5 1 238.5 4.2 2 471.2 7.0 3 85.0 2.5 4 453.6 6.7 5 291.3 3.8 6 232.5 2.9 7 346.7 4.8 8 411.3 5.6 9 614.6 8.8 10 502.8 6.3 11 261.5 3.8 12 254.4 3.6 13 503.4 6.7 14 207.6 3.3 15 144.6 3.6 16 175.0 6.0 17 211.7 3.8 18 98.0 4.3 19 316.7 5.1 20 259.7 4.2 21 270.3 4.0 22 77.0 5.2 23 142.3 4.0 24 245.2 4.0 25 129.2 3.9 26 54.8 8.9 27 236.4 3.8 28 215.0 4.8 29 100.4 9.9 30 72.4 8.5 31 146.3 6.5 32 228.4 5.8 33 143.3 6.5 1 169.3 2.6 2 139.2 2.3 3 428.2 6.4 4 459.5 5.8 5 235.6 3.6 6 350.9 4.9 7 432.1 5.5 8 315.3 5.5 9 616.3 8.0 10 236.1 3.2 11 175.3 2.8 12 314.9 4.2 13 384.7 5.0 14 621.0 8.1 15 437.8 6.6 16 320.7 5.5 17 203.9 4.2 18 283.6 4.4 19 215.3 3.8 20 56.6 8.5 21 149.6 4.4 22 198.2 3.4 23 135.3 3.4 24 150.7 3.4 25 127.5 4.0 26 107.3 4.2 27 133.2 5.6 28 245.9 4.2 29 22.8 10.9 30 51.9 12.7 31 48.9 14.2 132 302.9 5.6 33 227.5 6.5 1 328.2 4.8 2 160.4 2.5 537.4 7.4 183.2 3.1 616.9 8.0 295.8 4.7 530.7 7.0 541.2 7.9 315.0 4.0 945.2 12.4 148.8 2.7 145.2 2.8 246.1 3.6 275.6 4.3 171.1 4.0 409.1 6.0 511.6 9.5 487.8 7.2 280.2 4.5 152.1 3.6 108.0 4.6 204.9 3.8 170.0 3.9 212.9 3.6 219.5 3.9 51.7 10.0 198.4 4.2 214.7 5.0 19.3 9.6 82.9 6.9 216.3 4.5 99.1 8.4 286.6 7.3 341.3 4.9 233.2 3.2 217.7 3.3 248.9 3.8 295.5 4.1 569.8 10.0 644.7 8.8 587.2 7.9 633.2 9.9 I431.7 6.6 645.5 8.8 363.8 5.3 286.3 4.2 142.7 8.4 327.7 4.8 374.0 5.8 284.9 4.4 1276.8 4.4 172.6 3.9 193.1 3.6 119.8 5.7 131.4 3.4 1. 268.7 4.2 I 145.6 3.8 i189.2 3.6 i213.2 3.8 7 112.5 4.5 3100.4 7.4 29.1 13.0 83.0 6.6 1 236.9 5.0 Z 64.0 13.1 3 97.0 8.9 454.7 7.5 505.9 7.0 155.2 2.6 190.6 2.7 ;60.0 3.1 i216.0 3.2 F332.8 5.6 1579.8 7.4 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 125 12 112 129 130 14 15 16 17 18 19 914 91 9 1: 9 1 9 1 9 1 107.5 265.9 1056.5 518.2 410.5 314.9 586.8 442.8 150.9 315.1 364.6 123.2 12.9 190.0 237.6 187.0 228.3 46.6 30.5 1 129.9 96.8 252.6 39.3 1 190.0 156.6 382.9 94.1 441.3 231.0 419.0 255.5 320.6 169.0 404.9 496.2 602.9 139.2 488.6 184.9 327.5 584.9 382.0 163.5 229.0 144.2 284.8 456.1 75.3 240.4 126.1 262.1 221.9 115.5 476.1 74.8 206.9 -83.5 287.5 53.4 199.5 231.4 253.3 598.2 158.1 524.2 309.1 0 237.5 1 495.5 2 185.7 3 158.7 4 260.8 5 181.3 2.9 3.8 14.9 4.7 9.8 6.7 3.7 4.4 5.7 3.9 3.7 3.9 3.7 9.7 .2.4 7.8 6.9 4.9 4.1 5.4 6.7 2.4 6.1 3.1 5.8 3.7 3.9 2.8 5.9 7.6 8.4 2.8 6.1 3.4 5.3 9.2 7.2 3.7 3.8 6.8 4.8 3.8 4.4 4.1 3.9 11.6 7.9 8.4 11.9 5.4 3.2 2.9 3.4 3.4 9.1 2.6 4.6 4.4 3.2 3.7 4.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -83- 365.2 5.5 378.0 5.9 61.1 5.4 380.6 5.5 133.3 3.7 288.0 4.1 51.8 6.3 77.4 4.6 150.0 4.0 60.5 7.9 190.1 3.6 26.1 10.8 225.2 8.7 135.5 4.6 353.8 6.6 68.5 11.2 151.2 7.2 14.9 6.8 373.0 6.0 823.6 15.3 74.2 2.9 273.8 3.8 496.9 6.5 461.8 6.1 791.2 9.5 884.3 12.9 86.5 3.2 656.2 9.5 678.8 8.6 520.4 7.2 623.1 7.9 616.2 8.8 582.9 8.6 213.2 3.6 388.4 7.1 225.0 3.9 P353.6 5.1 136.1 3.6 221.2 3.6 127.7 4.4 195.9 3.5 127.1 3.9 214.3 3.8 113.5 4.2 162.4 14.9 I211.3 4.5 204.2 5.4 143.3 6.0 32.5 13.7 506.3 8.3 168.3 2.9 659.1 8.7 280.2 3.9 223.9 3.0 456.8 6.6 1086.8 16.4 388.0 5.9 675.6 9.1 )626.6 9.9 1 228.1 3.4 Z 313.3 4.8 3 426.1 5.6 4 606.5 8.9 391.3 6.3 340.6 5.3 7 426.4 6.6 8 175.9 4.3 9 239.7 4.1 D 234.6 4.4 1 261.4 4.1 2 107.6 4.2 3 139.7 3.6 24 409.5 5.9 25 243.4 4.0 26 24.5 10.9 27 143.3 5.0 28 61.7 9.1 29 119.2 5.8 30 141.4 5.8 31 17.0 8.5 32 158.6 5.1 1 119.0 2.6 2 607.0 8.2 3 494.5 6.7 4 695.9 9.0 5 692.5 9.4 6 227.0 3.2 7 195.7 2.7 8 26.1 9.2 9 263.3 4.0 10 249.0 3.5 11 203.0 3.9 12 96.9 4.0 13 244.0 4.4 14 564.4 8.6, 15 307.3 4.5 16 349.1 5.3 17 219.7 3.6 18 228.4 3.6 19 237.8 4.2 20 313.9 4.6 21 273.1 3.9 22 102.4 3.7 23 40.7 8.2 24 302.7 4.5 25 183.6 3.6 26 164.2 3.8 27 142.2 14.9 28 212.9 5.0 29 96.2 6.6 30 172.8 5.4 31 106.2 6.5 32 90.3 7.4 1 452.8 7.2 2 158.5 2.5 3 668.0 10.5 4 869.7 11.2 5 166.6 2.4 6 480.1 6.1 7 398.7 6.3 8 771.1 11.6 9 423.2 5.4 11 589.0 8.5 12-251.4 4.5 13 358.4 4.7 14 512.3 7.8 15 243.7 4.1 16 101.1 4.5 17 222.2 4.1 18 314.1 5.6 19 332.5 4.7 120 164.7 3.4 1 21 364.5 5.6 1 22 159.2 3.2 1 23 154.1 4.1 ;24 131.4 3.5 1 25 81.1 5.8 1 26 329.9 5.9 327 284.5 12.4 1 28 180.0 4.1 3 29 157.5 4.8 3 30 74.4 13.7 3 31 55.4 13.4 4 1 108.7 5.2 2 575.2 8.3 3 388.1 5.1 4 294.2 4.3 5 638.8 9.4 6 359.0 4.7 7 841.8 11.8 8 517.1 6.2 9 406.1 5.8 10 249.3 3.8 11 73.2 5.2 12 402.2 5.9 13 268.7 4.2 14 337.8 5.5 15 417.9 6.4 16 191.1 3.4 17 82.8 5.7 18 324.4 5.1 19 113.4 3.5 20 158.9 3.3 21 266.2 4.1 22 238.6 3.5 23 110.2 5.0 24 273.0 4.2 25 254.5 3.8 26 314.7 5.1 27 155.5 5.3 28 141.7 5.0 29 71.6 7.8 30 141.4 5.7 31 84.4 13.2 1 119.1 2.8 2 337.1 4.4 3 882.1 12.4 4 370.4 4.8 5 364.2 4.9 6 393.9 5.7 7 499.7 7.3 8 335.7 5.7 9 65.3 5.8 10 466.7 6.6 11 547.7 7.5 12 171.9 3.3 13 848.7 11.6 14 158.4 3.3 15 326.2 4.7 16 164.5 3.0 17 356.6 6.0 18 110.6 3.6 19 146.7 5.2 20 306.1 4.3 21 266.9 3.8 22 230.8 3.7 23 157.1 4.0 24 168.8 3.7 25 51.3 8.4 26 37.1 17.0 27 299.6 5.2 28 190.3 4.4 29 158.8 5.1 30 168.2 4.9 31 23.2 10.9 *1 533.6 7.9 *2 446.0 7.0 3 527.1 7.6 4 496.1 6.3 5 560.8 9.0 6 754.5 9.3 7 341.8 5.0 8 524.8 7.9 i9 407.9 5.7 10 296.7 4.5 i11 263.8 4.1 16 12 2 16 13 2 16 14 5 16 15 1 16 16 2 16 17 2 16 18 1 16 19 1 16 20 1 16 21 16 22 1 16 23 1 16 24 1 16 25 3 16 26 2 16 27 16 28 1 16 29 16 30 1 16 31 2 17 1 7~ 17 2 6~ 17 3 6 17 4 6~ 17 5 3: 17 6 4* 17 7 3' 17 8 3.

17 9 1 17 10 4 17 11 17 12 1 17 13 17 14 17 15 17 16 17 17 17 18 17 19 17 20 17 21 17 22 17 23 17 24 17 25 17 26 17 27 17 28 17 29 17 30 18 1 6 18 2 3 18 3 1 18 4 3 18 53 18 6 18 7 1 18 8 18 9 18 10 18 11 18 12 p18 13 18 14 18 15 18 16 18 17 18 18 18 19 i18 20 i18 21 i18 22 20.6 03.8 04.6 57.5 10.5 41.2 37.5 83.3 31.5 39.9 58.2 21.7 55.5 20.2 .05.4 74.6 47.2 36.4 15.1 :20.2 85.9 20.2 43.8 38.4 33.9 74.8 97.0 31.6 80.9 192.1 83.0 180.2 140.0 ~32.7 166.7 100.3 176.2 183.9 !84.0 Z09.9 247.2 131.3 269.5 183.2 47.1 413.4 308.1 226.3 82.2 66.3 90.3 118.4 83.1 129.6 191.6 280.9 100.4 520.3 ?47.7 439.7 559.5 316.5 319.9 152.0 132.7 2 12.1 133.6 135 .0 298.2 254.4 158.9J 21 1A 3.6 3.7 3.

4.1 3.1 3.9 7.6 3.2 4.1 3.7 8.2 7.4 4.2 14.4 5.8 5.6 16.3 10.9 9.6 5.6 5.3 4.9 3.1 7.4 4.2 3.6 6.2 4.2 3.4 4.3 4.2 3.7 4.4 14.8 6.9 4.4 7.8 9.8 18.5 3.4 4.7 5.3 4.6 6.8 7.6 3.6 5.7 8.2 5.6 3.1 3.2 3.3 2.9 3.8 4.2 3.4 3.3 3.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -84- 23 141.4 .3.6 24 406.6 5.2 238.3 8.0 26 325.6 5.3 27 84.3 6.4 28 192.7 4.6 29 143.1 5.2 58.8 9.6 1 440.3 7.6 2 282.7 5.4 3 435.2 7.1 4 393.3 5.5 190.5 3.6 6 651.5 9.3 7 149.1 3.1 8 397.4 5.8 9 39.4 7.4 218.2 3.6 11 169.0 3.1 12 191.2 3.7 13 13.9 6.8 14 101.1 4.3 179.6 3.2 16 332.2 5.0 17 200.0 4.0 18 104.0 3.1 19 138.2 3.1 174.3 3.2 21 256.3 4.8 23 254.7 3.9 24 103.4 5.7 138.7 4.1 26 112.7 6.3 27 239.8 4.7 28 72.9 7.5 29 165.9 5.4 1 287.0 5.2 2 39.9 14.3 3 135.9 3.2 4 611.7 8.1 24.1 8.0 6 224.2 3.4 7 504.5 6.7 8 313.4 4.6 9 183.6 3.4 84.6 3.1 11 426.7 6.1 12 389.3 5.2 13 606.5 11.4 14 131.6 2.9 341.7 5.3 16 325.2 4.4 17 248.4 4.5 I18 116.4 3.0 19 78.2 4.5 282.5 4.0 21 80.2 5.1 22 101.5 5.1 123 174.0 3.5 124 198.2 9.3 1 25 330.6 5.6 1 26 338.4 5.4 127 187.4 4.1 28 74.7 8.5 29 41.0 12.2 1 46.2 5.2 1 2 406.7 6.9 1 3 392.5 6.0 1 4 227.7 3.3 1 5 444.7 5.8 1 6 15.6 7.1 1 7 302.0 3.9 8 259.6 3.8 9 111.6 3.1 10 269.3 3.9 11 216.0 3.6 12 58.4 6.0 13 220.3 3.6 14 242.8 3.8 15 168.3 3.4 16 337.7 5.5 17 259.1 4.0 18 187.2 3.0 19 57.3 5.1 20 181.8 3.3 21 167.0 3.7 22 69.6 4.9 23 174.7 7.7 24 36.6 12.8 25 123.1 4.5 26 240.1 4.7 27 79.8 8.6 28 108.8 6.8 29 216.6 6.4 1 332.8 5.7 2 584.6 12.1 3 204.7 6.3 4 215.0 3.1 5 130.0 2.5 6 409.6 5.1 7 256.2 3.6 8 234.9 3.4 9 203.0 3.4 10 205.7 3.1 11 472.3 6.6 12 308.6 5.0 13 91.1 3.4 14 284.4 3.8 15 412.0 5.5 16 47.9 5.4 17 272.3 3.9 18 178.1 3.2 19 79.6 4.5 20 215.7 3.6 21 125.8 3.5 22 191.1 3.6 23 124.5 7.7 24 137.3 4.4 25 275.8 5.2 26 123.7 4.4 27 38.7 13.1 28 53.7 9.8 1 414.2 8.4 2 92.4 4.3 3 80.7 3.5 4 512.0 7.1 15 105.2 2.4 16 174.9 2.6 1 7 34.9 6.5 18 253.1 3.5 19 159.9 3.1 110 106.3 3.0 311 58.8 4.5 3 12 327.8 5.9 3 13 213.0 3.1 3 14 324.8 5.3 3 15 205.2 3.9 3 16 295.6 4.2 3 17 22.3 8.9 3 18 167.7 4.5 3 19 105.7 3.5 3 20 181.9 3.8 3 21 18.8 8.5 3 22 197.9 9.1 -6 23 -6 23 -6 23 -6 23 -6 23 -6 23 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 24 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 25 -6 2( -6 2( -6 2( -6 2( -6 2( -6 24 -6 24 -6 24 -6 2i -6 2i -6 2 -6 2 -6 2 -6 2 23 139.5 24 34.7 1 25 73.37 26 90.18 27 101.4 28 221.5 1 213.6 2 434.9 3 324.4 4 465.0 5 293.9 6 178.1 7 201.1 8 250.8 9 391.8 10 124.3 11 282.8 12 204.7 13 49.1 14 20.3 15 368.1 16 97.8 17 145.2 18 46.9 19 208.2 20 131.9 21 21.4 1 22 29.9 1 23 70.6 24 303.0 25 146.8 26 164.7 27 158.1 1 235.6 2 274.6 3 198.8 4 348.6 5 322.2 6 127.5 7 99.0 8 47.0 9 29.1 10 265.0 11 101.5 12 74.5 13 85.6 14 253.2 15 189.0 16 65.1 17 116.4 18 49.6 19 132.7 21 117.0 22 98.7 23 160.0 24 88.9 25 259.6 26 53.1 1 474.7 2 229.6 S3 92.6 5 4 375.0 5 5 178.0 6 6 191.9 6 7 214.6 6 8 103.8 6 9 165.5 6 10 170.8 6 11 97.5 6 12 154.2 6 13 287.8 6 14 237.7 4.3 2.4 1.7 6.8 5.7 1.4 .5 i.0 3.7 3.0 3.1 3.5 5.3 2.4 4.0 3.0 1.4 7.9 5.1 3.0 2.8 6.4 3.8 3.5 0.2 1.5 6.9 5.5 4.5 6.0 4.6 5.4 7.5 7.2 5.4 4.0 2.4 t.2 7.7 3.9 2.5 4.0 3.3 3.6 3.0 3.9 3.0 6.2 3.2 4.2 4.9 5.0 5.5 4.8 9.6 8.9 5.2 5.5 8.1 2.8 2.7 3.0 2.5 2.5 2.8 2.6 2.6 4.1 3.3 115.0 2.7 77.1 3.8 181.8 3.2 165.2 3.1 26.8 445.9 148.3 3.6 61.7 7.6 226.5 4.4 40.5 15.7 125.7 109.9 5.4 329.1 6.6 282.9 5.3 297.4 5.9 291.2 4.6 313.5 4.7 70.5 3.1 512.1 6.2 365.7 4.8 245.7 3.2 275.9 80.0 2.9 246.4 4.1 120.8 214.4 3.2 144.8 169.5 3.3 182.1 3.2 18.2 4271.8 1 129.0 133.3 3.4 t154.6 179.0 6.1 1 175.6 4.8 i141.9 5.6 255.0 5.3 163.6 189.5 4.2 209.7 3.3 73.5 2.6 240.0 3.6 77.8 2.7 96.0 2.6 128.7 2.4 3 161.7 2.6 1 91.7 2 191.3 3 120.1 2.6 41 159.6 2.8 5 259.0 3.9 6 61.4 4.1 7 292.4 5.4 8 164.9 8.9 9 247.0 0 186.9 1 62.1 6.1 2 65.7 3 71.1 6.2 4 78.2 1 406.0 7.9 2 267.3 4.9 3 74.0 4 146.5 2.8 5 85.3 2.2 6 228.7 3.2 7 229.2 3.2 8 194.2 2.6 9 139.1 2.3 0o 129.4 2.6 [1 205.6 SUBSTITIUTE SHEET (RULE 28) WO 99/10379 WO 990379CT/GB98/02542 217.6 3.3 110.5 2.7 28.1 7.8 187.4 3.3 63.2 12.2 108.8 4.0 165.3 4.2 205.2 3.7 335.1 5.6 190.4 4.0 188.1 3.8 162.1 4.2 97.9 3.5 218.7 4.0 339.5 7.4 305.8 6.1 194.9 3.9 100.8 2.3 197.3 3.0 51.6 4.8 219.6 3.2 101.5 2.6 235.8 3.6 201.6 2.9 198.4 2.9 303.3 5.0 187.4 3.7 347.9 5.8 116.8 3.1 93.5 3.5 178.2 3.6 227.4 4.2 197.1 3.6 164.3 3.8 68.6 7.2 137.5 2.9 192.0 4.7 107.8 3.5 60.3 7.6 231.5 3.8 47.6 3.8 172.8 2.7 108.2 2.3 126.7 2.7 101.6 2.5 181.9 2.7 228.0 3.6 153.6 2.9 168.3 10.9 297.9 4.1 156.3 3.2 46.4 7.4 1175.0 3.9 150.7 3.7 227.6 4.1 161.1 3.8 90.8 5.0 138.8 3.4 85.7 3.8 178.2 3.8 253.8 4.6 64.0 3.3 221.6 3.8 52.2 3.6 229.3 3.5 235.5 4.2 )92.3 2.7 1 47.5 5.3 2 135.5 4.1 3 114.6 7.6 1 56.6 4.2 85.4 3.6 123.3 2.9 152.3 3.1 95.2 4.7 116.2 3.8 68.4 6.2 112.8 4.5 54.6 4.6 164.0 3.4 69.6 4.8 221.3 4.3 108.0 4.7 35.5 7.9 64.3 2.9 142.5 2.4 76.8 2.9 134.6 3.9 154.2 6.5 17.2 7.6 100.7 2.7 306.2 4.3 194.0 3.3 60.5 5.0 187.0 3.4 99.5 4.6 50.0 6.5 55.2 7.1 261.3 6.2 164.8 3.9 55.4 5.2 51.9 5.9 144.0 4.0 14.0 6.7 278.7 4.8 84.6 8.3 92.1 3.0 136.3 3.0 174.4 3.1 106.6 3.1 105.7 2.9 80.8 4.2 89.0 3.9 142.2 3.6 47.1 8.9 92.4 4.5 191.6 8.4 97.4 7.4 217.5 10.9 262.2 9.7 69.0 9.5 231.5 3.8 59.5 3.8 143.3 2.6 1 115.3 2.6 116.8 3.0 48.8 5.6 65.6 4.2 1202.5 3.8 i56.5 6.9 i101.4 3.6 F 58.1 6.1 159.6 9.0 57.9 4.6 16.8 7.7 89.9 3.9 113.3 3.5 124.2 3.5 67.3 4.7 74.2 3.9 100.7 2.9 186.2 3.2 D 115.1 2.7 1 81.5 3.5 -6 36 -6 36 -6 36 -6 36 -6 36 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 37 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 38 -6 39 -6 39 -6 39 -6 39 -6 39 -6 39 -6 39 -6 39 -6 39 -6 39 -6 39 -6 40 -6 40 -6 40 -6 40 -6 40 -6 40 -6 40 -6 40 -6 41 -6 41 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 -5 0 12 140.8 13 173.2 14 139.8 15 182.5 16 16.5 1 274.4 2 50.0 3 165.6 4 164.9 5 138.7 6 173.3 7 127.2 8 96.8 9 225.8 10 153.0 11 125.5 12 102.8 13 136.7 14 271.2 15 100.5 1 131.7 2 126.4 3 204.6 4 136.0 5 84.5 6 177.5 7 51.5 8 63.5 9 88.9 10 58.4 11 191.8 12 59.0 13 55.5 1 95.3 2 116.1 3 140.8 4 66.6 5 207.9 6 106.7 7 69.1 8 142.5 9 204.8 10 92.2 11 110.6 1 129.1 2 134.5 3 189.4 4 67.5 5 179.0 6 103.7 7 235.4 8 63.6 1 37.9 2 72.2 1 400.8 2 425.2 3 413.6 4 52.1 5 223.5 6 361.9 7 517.5 8 95.0 9 221.1 10 95.4 11 134.9 12 39.3 13 869.5 14 521.2 15 263.1 16 189.2 17 222.8 2.7 3.0 3.4 3.3 7.8 6.1 9.5 3.9 6.8 5.4 3.6 3.0 2.3 3.6 3.4 2.7 3.2 2.7 4.5 5.4 4.8 4.9 4.2 4.0 4.2 3.7 4.8 3.3 3.3 4.1 3.3 4.4 5.5 5.1 6.4 5.5 8.3 7.3 3.4 4.0 2.9 3.4 3.0 4.6 4.0 4.2 7.7 7.2 3.9 3.4 5.6 4.8 9.6 11.5 8.6 8.8 9.8 4.1 3.8 7.5 15.3 3.3 4.8 4.1 3.5 10.6 19.4 11.2 5.8 5.3 11.1 6.9 0 19 0 20 0 21 0 22 0 23 0 24 0 25 0 26 0 27 0 28 0 29 0 30 0 31 0 32 0 33 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 1 10 1 11I 1 12 1 13 1 14 1 15 1 16 1 17 1 18 1 19 1 20 1 21 1 22 1 23 1 24 1 25 1 26 1 27 1 28 1 29 1 30 1 31 1 32 1 33 2 1 2 2 2 -3 2 4 2 5 2 6 2 7 2 8 2 9 2 1( 2 1 2 1 2 1~ 2 1 2 1: 2 1i 2 1 2 1.

*2 1 2 2 2 2 2 2 i2 2 i2 2 267.9 45.4 1 306.0 177.3 128.6 365.8 286.7 237.6 87.8 164.4 14.9 1 47.7 2 249.2 187.7 223.6 510.5 418.0 381.2 120.8 173.2 104.8 236.5 151.0 363.7 277.2 289.9 541.8 419.7 370.5 242.5 420.0 465.2 468.7 407.2 455.3 580.7 389.6 130.7 443.2 157.8 93.6 270.2 178.5 I96.1 202.8 118.7 358.6 28.9 414.3 465.5 407.0 295.1 368.2 421.9 426.8 397.9 357.6 )447.5 1 339.6 2 639.1 3 179.2 4 495.8 5 591.4 6 367.2 7 225.0 8 763.1 9 221.2 0 370.3 1 65.0 2 341.8 3 78.6 4 127.7 7.3 5.7 5.4 9 .6 6.2 1.1 :2.7 7.3 8.1 7.9 5.8 7.1 2.2 2.3 2.1 4.1 3.6 6.3 5.7 3.9 5.8 6.4 5.7 6.7 8.1 4.3 6.2 6.2 14.3 4.8 6.1 5.6 13.5 7.8 6.4 5.2 4.4 5.1 6.3 5.8 5.3 5.3 5.7 5.1 9.1 2.9 7.4 8.7 5.2 9.9 5.7 6.8 5.3 4.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 222.6 3.9 165.0 4.3 77.5 8.0 156.2 4.7 212.3 17.3 214.8 5.5 205.0 5.1 82.0 9.9 269.9 6.4 111.9 2.4 463.7 6.1 326.6 4.2 254.3 3.7 200.4 3.2 264.3 4.4 320.7 4.3 228.2 3.3 247.9 3.9 59.1 4.5 372.2 5.3 526.2 7.5 66.0 5.2 309.3 4.3 134.2 3.5 541.7 7.4 181.7 4.5 182.9 3.5 644.3 10.2 369.4 5.7 219.2 3.7 115.9 3.9 101.1 5.4 220.2 4.7 281.5 4.9 164.0 3.8 19.7- 9-.5 246.6 4.2 334.2 16.4 I97.4 7.9 108.7 6.4 205.4 5.6 1135.7 6.8 473.4 6.9 507.0 7.7 173.6 3.0 146.6 2.3 504.6 7.9 135.8 2.7 236.2 3.7 439.4 6.3 738.8 9.5 260.3 3.5 1389.5 5.9 586.9 10.4 67.6 4.4 1 619.7 8.7 288.7 4.7 557.5 7.5 7 390.9 5.6 3 777.7 10.8 468.8 6.9 D 657.4 9.6 1 155.5 3.6 2 112.8 3.9 3 179.9 4.3 4 94.2 5.1 59.7 7.3 6 134.8 4.3 7 125.7 4.4 8 184.4 4.5 9 341.5 12.6 0 75.6 9.9 148.7 5.4 151.6 6.7 47.5 15.0 432.9 6.0 491.7 6.8 478.3 7.5 261.6 3.8 10.9 5.2 262.5 3.7 388.7 5.7 279.0 4.2 169.5 3.1 563.2 7.8 402.9 6.4 412.1 5.9 82.0 4.4 461.2 6.9 511.1 7.5 206.5 3.7 226.2 4.3 203.6 4.0 353.9 5.9 244.1 3.8 192.2 3.8 121.1 4.6 293.1 5.0 288.6 4.4 53.1 7.9 256.1 4.2 136.3 4.2 262.6 4.4 306.3 11.0 1114.5 5.6 140.0 5.7 25.1 12.3 175.7 6.4 70.4 2.6 86.8 2.2 258.6 3.5 169.6 2.9 420.2 5.1 190.4 2.6 110.0 2.2 164.3 2.9 307.1 4.6 )534.3 7.2 1 325.3 5.3 Z 178.6 3.0 3 334.1 5.7 1 324.2 4.7 5 420.7 6.1 5 729.4 10.9 7 256.1 4.4 8 25.3 11.7 9 120.7 3.7 D 137.6 4.0 1 287.3 4.4 2 174.4 3.5 3 66.0 7.2 4 102.4 4.9 5 253.9 4.8 6 448.6 6.4 7 73.4 8.8 8 248.3 4.4 9 344.8 9.4 0 152.5 4.8 1 49.8 12.7 2 26.9 12.9 3 216.4 5.3 1 423.9 6.3 2 353.0 5.2 3 548.6 7.3 260.5 3.7 152.0 2.6 141.9 2.3 420.0 5.5 207.8 3.0 781.1 10.0 457.6 6.6 349.4 5.0 126.3 3.2 366.8 5.6 165.0 3.9 537.7 7.3 374.9 5.5 185.0 3.5 341.3 5.2 20.0 9.0 356.0 4.9 104.8 4.1 268.2 4.5 237.5 4.5 170.1 3.7 73.5 6.8 143.7 4.1 205.0 4.7 135.9 5.0 165.2 8.4- 195.6 4.7 73.2 8.0 187.3 5.9 134.0 7.3 250.0 3.8 157.8 2.3 229.9 3.2 422.2 6.2 253.7 3.9 291.7 4.0 338.8 4.8 215.7 3.4 305.0 4.6 749.1 11.3 1265.4 4.0 Z624.2 8.5 254.1 3.6 1 398.9 5.5 5 276.8 4.0 5 265.3 3.8 7 678.8 11.0 9 451.4 7.3 101.2 4.0 D 340.7 4.9 1 302.2 4.6 2 413.0 6.4 3 79.7 5.6 4 384.4 5.4 5 133.7 4.8 6 178.4 5.8 7 157.9 3.9 8 25.1 11.3 9 41.7 15.9 0 104.7 6.5 1 121.0 6.1 2 116.6 6.7 3 225.3 5.1 1 270.6 4.2 2 491.2 7.6 3 352.2 4.7 4 167.7 2.7 5 256.5 3.7 6 512.1 6.9 7 398.7 5.6 8 598.7 7.8 9 584.5 8.7 10 265.8 3.6 11 984.5 13.8 12 612.2 13 402.9 5.4 14 257.9 15 86.1 5.6 16 378.1 5.8 17 225.6 3.9 18 483.8 19 72.2 20 164.9 3.6 21 310.0 4.7 22 232.4 3.7 23 155.4 3.6 24 91.0 6.2 25 166.9 26 58.6 27 108.6 4.6 28 56.5 17.0 29 238.8 4.6 30 118.4 6.3 31 245.3 32 146.3 33 82.3 8.9 1 575.0 10.1 2 137.1 2.3 3 579.4 9.7 P4 398.8 4.8 I5 112.7 2.3 6 266.9 4.6 7 442.6 5.8 8 501.8 8.3 I9 1272.4 17.0 1 10 503.5 8.8 I11 301.8 4.2 I12 658.3 13 593.8 9.3 14 159.0 3.2 15 212.1 4.4 16 479.6 6.7 17 456.0 7.7 18 219.3 3.6 )19 458.6 6.3 )20 177.7 )21 144.2 3.6 )22 331.9 4.9 323 232.5 4.4 324-97.9 325 185.8 5.4 D 26 97.6 4.6 D 27 44.8 12.6 0 28 274.6 13.3 0 29 340.4 5.6 0 30 282.5 5.7 0 31 189.4 4.9 0 32 100.8 7.6 1 1 70.5 2.4 1 2 444.8 5.6 1 3 413.4 1 4 326.3 4.8 1 5 419.7 5.7 1 6 428.8 6.6 1 7 613.9 8.6 1 8 670.8 8.3 1 9 351.4 4.9 1 10 226.9 3.3 1 11 1076.4 13.6 1 12 600.9 8.3 1 13 114.0 1 14 591.6 8.4 1 15 519.8 9.1 11 16 427.9 6.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 151.5 4.7 424.3 6.1 489.4 7.6 622.6 10.0 78.4 5.5 284.3 4.5 51.9 7.9 376.7 5.9 324.0 6.3 96.7 4.8 55.8 8.2 288.2 10.6 22.4 11.0 280.3 4.9 126.3 5.8 253.5 4.7 521.1 6.9 216.6 3.0 488.9 6.3 399.7 5.5 623.9 8.9 430.7 5.8 363.6 4.9 130.1 2.4 281.0 4. 3 251.5 3 .5 712.8 10.2 521.7 8.9 193.8 3.8 339.9 5.3 167.0 3.2 656.9 11.0 183.4 3.2 168.1 3.4 240.8 4.0 193.4 3.4 406.2 5.8 82.9 4.7 248.6 4.2 75.9 5.4 139.8 5.0 340.6 5.1 157.0 4.4 259.3 5.4 33.0 14.1 145.9 4.8 104.9 7.2 89.0 8.8 154.2 2.9 220.4 3.2 315.2 4.2 573.1 7.0 306.0 4.1 243.9 3.8 573.6 7.7 708.6 10.1 306.1 4.4 264.8 3.9 182.6 3.1 342.6 5.1 625.9 8.9 126.0 3.8 286.7 4.8 248.7 3.8 215.6 3.7 134.4 3.3 P148.2 4.0 I114.9 4.2 269.2 4.1 68.9 6.0 104.4 5.0 138.1 4.2 25 77.1 5.6 26 117.3 5.7 27 21.4 10.6 28 308.3 5.8 29 223.5 4.9 30 83.1 10.3 31 61.4 12.9 32 105.3 7.7 1 240.1 6.3 2 390.5 5.3 3 873.0 13. 8 4 707.9 9.5 5 371.0 4.5 6 701.7 10.0 7 389.6 5.5 8 259.9 3.4 9 926.3 15.8 10 914.2 12.6 11 453.8 7.9 12 35.2 8.9 13 494.3 7.0 14 523.9 9.4 15 58.0 5.5 16 257.0 4.6 17 219.0 3.6 18 215.8 3.6 19 302.4 4.4 20 197.5 3.5 21 148.8 3.2 22 100.8 4.5 23 177.2 3.5 24 156.2 4.2- 25 340.3 5.3 26 256.7 4.4 27 563.7 8.1 28 *78.2 6.8 29 79.5 7.1 30 83.2 11.6 31 30.0 13.7 32 108.0 8.5 1 151.7 2.9 2 448.9 5.7 3 668.0 10.2 4 66.8 3.1 5 340.0 4.6 6 563.9 8.6 7 251.1 3.6 8 362.2 4.8 9 605.1 9.3 10 217.7 3.6 11 553.6 7.7 12 298.9 5.5 13 103.6 4.0 14 666.2 10.1 15 659.6 9.4 16 216.4 3.6 17 328.1 5.3 18 226.3 3.3 19 170.8 3.1 20 219.6 4.3 21 241.2 3.6 22 90.0 5.3 23 234.3 3.9 24 105.2 4.3 25 210.4 4.0 26 132.8 4.1 27 140.1 6.8 28 112.5 6.6 29 302.6 6.2 30 156.9 4.8 31 57.0 11.8 1 218.2 3.7 2 718.4 10.4 3 203.0 3.6 4 696.7 8.6 5 656.6 9.2 6 888.3 13.1 7 128.5 2.3 8 269.3 4.2 9 178.6 3.7 10 327.2 4.8 11 193.6 4.8 12 364.7 5.5 13 269.6 5.0 14 393.5 6.3 15 239.7 3.9 16 205.1 3.5 17 255.1 3.7 18 185.5 3.5 19 226.2 4.3 20 165.2 4.3 21 408.4 6.0 22 204.5 3.5 23 70.6 5.7 24 138.5 4.0 25 119.5 5.0 26 36.5 15.3 27 45.8 10.9 28 135.2 5.2 29 130.3 5.6 30 102.3 7.5 31 111.4 6.1 1 356.2 6.1 2-438.8 6.5 3 .88.3 2.3 4 1252A 14.1 5 548.1 7.9 6 866.7 10.7 7 787.1 10.2 8 605.4 8.0 9 123.3 2.6 10 420.5 5.8 11 217.9 3.5 12 154.2 3.0 13 376.8 5.4 14 327.3 4.6 15 395.0 5.4 16 195-.2 3.3 17 291.2 4.6 18 269.9 4.0 19 120.2 3.3 20 73.5 4.5 21 157.1 3.2 22 138.4 4.5 23 66.1 6.3 24 242.8 4.0 25 114.5 4.8 26 214.7 15.3 27 269.8 4.7 28 172.0 6.0 29 244.5 5.7 30 171.5 5.8 31 120.2 10.6 1 355.8 6.4 2 247.9 4.8 3 126.9 2.1 4 424.7 5.2 5 272.0 3.9 6 164.6 3.6 7 372.7 5.1 8 366.1 5.2 9 452.8 5.8 10 302.9 4.1 11 334.9 4.5 11-1.0 3.1 433.5 262.2 4.2 89.6 318.7 4.3 196.8 3.4 171.3 3.1 76.3 4.4 103.5 4.4 255.2 3.6 191.5 3.9 252.5 110.5 4.8 100.9 7.2 164.5 5.2 283.0 4.4 62.8 11.5 42.2 12.7 113.2 5.6 228.4 6.4 474.9 7.4 290.1 6.7 434.9 5.6 155.2 2.9 18.3 8.3 480.9 6 .8 58.8 4.6 429.1 6.1 I519.5 65.1 4.1 72.8 283.0 3.8 135.1 3.1 294.3 4.3 16.1 7.4 115.9 1228.3 3.6 250.7 3.7 217.4 3.6 151.9 3.6 t191.9 3.6 1130.9 I 382.5 5.9 i384.7 11.2 i160.6 4.1 7 90.1 5.8 181.6 11.3 )279.4 )33.2 14.0 521.9 10.0 11.5 5.7 373.1 5.3 237.5 3.9 302.6 4.4 185.9 426.9 7.4 102.8 3.3 I272.4 3.9 3 226.4 3.8 1 29.4 7.6 2 188.3 3 150.9 2.9 4 282.3 5 216.9 6 189.0 7 382.4 5.6 8 171.9 3.1 9 151.5 3.6 0 121.2 3.4 1 317.4 4.7 2 99.0 4.1 3 352.5 5.8 SUBSTITUTE SHEET (RULE 28) WO 99/10379 WO 9910379PCT/GB98/02542 -88- 130.9 .7.4 257.5 4.8 118.2 5.8 131.7 5.7 70.6 7.9 167.7 4.5 495.8 9.6 438.0 12.3 261.9 3.7 941.3 11.8 16.8 7.3 456.4 7.4 384.4 5.7 542.4 8.6 102.5 2.6 265.0 4.1 87.2 3.3 523.2 7.9 232.5 3.9 301.6 4.2 257.9 3.6 60.2 4.0 76.9 5.1 61.0 4.6 197.5 3.2 312.9 4.5 174.0 3.3 55.6 7.4 39.2 12.2 327.1 8.1 124.5 4.7 226.6 5.2 133.7 4.5 45.5 16.0 37.8 13.2 95.6 4.0 598.6 12.3 114.7 2.8 235.4 3.6 247.6 3.7 406.4 6.0 318.2 4.4 372.0 5.3 75.9 3.1 192.1 2.9 326.9 4.6 202.7 3.3 345.3 5.0 271.1 4.0 581.1 8.3 151.8 3.0 100.3 2.9 1 226.5 3.3 99.0 4.0 212.1 3.5 213.6 4.3 195.8 3.7 129.7 13.9 1 123.6 5.8 142.8 4.3 46.1 12.9 7 66.7 8.1 3 151.7 6.2 308.2 6.2 455.6 10.0 576.7 11.2 87.4 2.3 201.6 3.2 198.5 3.2 422.0 6.3 297.4 4.1 I119.4 2.5 391.4 5.3 244.7 3.3 249.9 4.2 306.0 4.3 12.9 6.1 377.5 5.1 185.3 3.0 272.9 4.1 125.1 3.0 297.5 5.9 126.5 4.1 134.1 3.8 81.9 6.5 57.7 8.5 195.5 4.0 179.2 5.1 149.9 5.7 166.3 4.9 358.6 6.8 98.7 3.1 62.8 3.3 242.0 3.7 275.1 4.0 57.6 3.1 583.6 8.8 91.8 3.3 300.7 4.0 114.2 2.6 335.7 4.3 35.1 6.6 146.8 2.6 160.9 3.1 408.3 5.8 71.8 4.4 347.0 4.9- 238.9 3.6 19.6 8.3 77.4 4.9 15.6 7.6 162.4 9.3 278.8 4.6 266.7 4.6 246.0 4.3 150.3 4.4 285.0 5.3 134.2 3.1 231.7 4.0 239.1 3.7 135.8 2.3 594.3 8.4 258.1 3.4 119.3 2.2 421.0 6.6 108.1 2.5 20.9 8.6 1 267.8 3.4 Z~ 76.8 3.4 3122.1 2.7 t 149.0 2.7 5 50.2 5.2 5 63.4 4.0 7 83.2 4.0 9 274.7 4.3 S179.0 3.4 D 117.7 4.0 1 167.4 10.2 2 60.4 7.6 3 17.1 8.5 4 69.4 7.9 5 135.0 5.1 6 41.5 12.4 7 82.3 6.9 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5: -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 1 130.0 3.0 2 387.7 7.2 3 101 .6 4.3 4 264.2 3.5 5 208.8 3.0 6 166.0 2.5 7 133.7 2.3 8 384.2 5.4 9 58.2 4.3 10 411.4 5.9 11 94.6 2.5 12 282.1 3.8 13 166.8 2.8 14 170.7 2.8 15 246.7 3.4 16 130.0 2.9 17 37.1 7.8 18 160.8 3.4 19 71.9 4.6 20 64.3 9.1 21. 374.9 5.7 22 274A4 5.1 23 252.5 4.9 24 27.8 10.9 25 171.1 4.6 26 177.2 4.3 1 246.5 4.7 2 81.7 3.2 3 323.9 6.0 4 235.6 4.0 5 211.6 3.3 6- 433.3 6.2 7 340.9 4.3 8 391.6 5.8 9 171.8 2.7 10 205.8 3.1 11 217.6 3.2 12 168.9 2.6 13 100.3 3.6 14 33.5 7.5 15 193.4 3.6 16 145.3 2.9 17 249.1 3.7 18 115.0 3.6 19 228.3 5.8 20 239.6 4.1 21 297.4 4.8 22 137.1 4.5 23 108.2 4.7 24 318.6 5.2 25 44.2 12.6 26 76.0 8.3 1 169.5 3.8 2 187.4 4.1 3 121.0 4.0 4 239.9 4.0 5 321.6 4.2 6 158.6 2.4 7 136.3 2.4 8 17.5 7.3 9 248.0 3.8 10 251.4 3.2 11 165.0 2.5 12 111.2 2.4 13 105.7 2.5 114 62.0 4.4 :15 24.3 7.9 116 47.8 6.5 17 169.9 3.1 118 75.3 4.6 1 19 82.7 6.9 1 20 142.9 3.4 39.4 11.2 186.6 3.8 229.6 3.9 75.2 6.4 146.9 4.7 99.0 3.1 154.5 3.3 402.2 8.1 201.8 3.2 110.5 2.4 282.7 3.8 108.7 2.1 117.1 159.0 2.8 73.7 3.3 76.9 3.6 212.2 3.8 46.0 7.2 81.9 5.6 157.7 3.1 162.7 4.4 124.2 114.9 4.4 121.1 76.1 5.6 130.5 4.3 63.3 8.6 193.4 3.8 165.1 3.1 154.2 3.1 28.2 7.9 169.8 3.7 153.8 2.4 66.8 2.9 130.7 2.1 147.4 2.8 213.9 3.1 107.7 2.4 141.3 2.4 165.8 3.2 188.1 3.6 35.7 7.4 59.1 4.3 168.5 11.5 29.4 9.8 1110.9 3.6 234.2 3.9 101.6 4.2 1181.1 4.1 !81.5 5.3 1 283.5 5.7 129.1 2.7 148.7 218.5 3.6 347.2 7.4 90.5 3.4 112.8 137.5 2.2 316.9 118.0 3 168.2 3.1 1 173.6 2.8 2 160.9 3.1 3 187.5 3.8 4 243.7 3.7 5 249.9 5.2 6 9.9 7 141.0 3.3 8 133.7 4.2 9 278.6 5.6 0 80.8 5.3 1 71.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 31 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 33 33 33- 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 i34 i34 i34 i34 i 3i 3 3 3z 3z 3z 3: 3: 53: 3: 3, 3, 3 3 3 3 22 85.8 5 1 114.3 2 2 97.0 2.

3 154.1 3 4 234.0 4 5 200.8 3 6 44.8 3 7 131.7 2 8 293.6 4 9 99.13 10 124.3 11 136.6 12 92.7 3 13 94.7 3 14 251.3 15 132.5 16 108.8 17 129.8 18 51.5 19 191.2 20 154.9 21 245.5 1 137.3 2 170.6 3 243.9 4 149.1 5 205.9 6 68.3 2 7 178.8 8 149.9 9 55.3 3 10 104.5 11 127.5 12 245.2 13 64.4 14 73.7 15 202.5 16 111.9 17 106.7 18 109.8 19 102.7 20 109.7 1 90.9 2 111.4 3 137.5 4 228.6 5 226.3 6 190.7 7 60.3 8 93.6 9 91.7 10 338.9 11 88.3 12 67.1 I13 161.8 14 97.8 I15 191.7 16 54.0 17 82.2 I18 60.5 t 19 46.6 5 1 109.0 5 2 60.7 5 3 172.3 5 4 223.1 5 5 100.1 5 6 141.4 5 7 175.5 5 8 146.0 5 9 112.2 5 10 82.6 11 172.2 .8 .6 .7 1 .6 '.5 .0 .,2 .2 2.2 2.5 1.2 1.8 5.8 2.8 3.6 3.1 4.4 4.0 4.5 2.8 3.4 4.2 3.0 3.4 .9 2.5 2.4 '.5 2.9 2.9 6.0 4.4 4.1 3.8 4.1 3.3 3.8 5.1 4.5 1.7 4.0 3.1 4.0 4.3 3.3 2.8 2.6 5.0 5.3 3.7 4.7 3.1 3.4 3.2 5.1 5.6 5.7 9.1 4.7 6.4 5.0 4.3 4.1 3.6 4.4 4.2 3.1 3.2 3.3 -5 3: -5 3: -5 3: -5 3: -5 3: -5 3: -5 3: -5 34 -5 34 -5 3' -5 3' -5 3' -5 3' -5 3' -5 3, -5 3 -5 3 -5 3 -5 3 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -5 3 -53 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6- 6 6 6 6 7 7 7 7 7 7 '7 '7 17 17 17 17 17 17 18 18 38 38 38 38 38 38 38 38 38 3' 38 39 49 49 44 44 49 4 12 72.0 3 13 92.73 14 75.9 15 87.03 16 235.6 17 179.0 18 19.25 1 273.9 1 2 133.1 3 219.2 4 85.0 6 5 161.4 6 114.5 7 90.4 2 8 70.2 2 9 100.1 10 359.1 11 277.1 12 104.7 1-3 109.8 14 101.3 15 82.5 16 356.8 17 24.21 1 215.8 2 47.0 3 185.3 4 178.1 5 55.0 6 158.6 7 84.0 8 88.7- 9 147.6 10 79.4 11 103.9 12 39.6 13 64.5 14 83.6 15 182.3 1 90.3 3 126.8 4 46.4 5 21.5 6 50.3 7 89.3 8 170.8 9 144.8 10 68.0 11 119.5 12 201.1 13 130.9 14 264.0 41 84.7 43 132.9 I4 51.2 5 210.1 46 152.1 7 57.7 8 20.0 )9 187.6 )10 170.5 11 154.4 9 12 188.4 0 3 93.6 0 4 98.8 0 6 155.5 01 7 179.8 0 8 84.4 0 9 203.8 0 10 95.7 1 4 111.8 1 5 51.2 1.7 1.9 1.0 1.6 4.0 3.4 0.0 8.4 5.5 .0 4.3 2.3 .9 2.6 5.4 3.8 3.0 3.4 3.3 5.7 5.1 10.6 7.2 1.4 5.4 6.2 8.0 6.6 2.8 2.8 2.6 2.8 3.1 7.3 4.1 4.5 4.3 4.4 6.4 9.5 9.8 5.2 2.7 2.9 2.4 3.2 2.9 3.4 3.3 4.5 4.4 4.3 9.2 8.1 5.2 4.7 8.2 3.0 2.8 2.8 3.4 4.3 4.7 4.3 5.7 3.0 3.1 5.3 4.1 7.4 -5 41 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 0 -4 C -4 C -4 C -4 C -4 C -4 C -4C -4C -4C -4C -4C -4C -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 6 71.0 9.7 1 319.8 6.7 2 248.2 6.5 3 282.5 6.4 4 527.8 11.3 5 407.5 8.6 6 77.4 3.7 7 44.7 4.4 8 187.3 3.8 9 328.9 7.1 10 612.3 10.4 11 544.0 14.0 12 481.2 8.7 13 55.4 5.7 14 795.2 15.3 15 588.5 12.2 17 230.4 5.0 18 253.5 5.9 19 230.9 5.6 20 638.4 11.5 21 60.9 12.3 22 287.7 7.3 23 134.4 5.3 24 285.1 6.7 25 182.0 5.2 26 11.3 8.4 27 103.2 11.5 28 73.2 13.9 29 159.0 7.5 30 191.2 8.3 31 156.2 7.5 32 533.3 11.8 33 199.8 9.0 34 161.4 7.1 1 300.7 4.7 2 375.4 6.6 3 151.8 2.4 4 291.4 4.6 5 276.4 4.1 6 383.9 5.4 7 639.6 10.2 8 193.4 3.0 9 158.4 2.6 10 166.2 2.4 11 284.2 3.8 12 96.4 2.8 13 633.8 9.5 14 169.2 3.3 15 337.5 4.8 16 295.7 5.0 17 113.6 4.2 18 305.6 4.8 19 723.2 11.5 120 215.2 3.7 1 21 199.4 4.0 1 22 195.8 3.7 1 23 550.6 7.5 1 24 146.2 3.7 1 25 84.9 5.0 1 26 72.9 7.4 1 27 231.1 4.8 1 28 96.1 8.7 1 29 63.2 14.8 1 30 243.6 5.6 1 31 149.7 5.2 1 32 158.2 6.2 1 33 117.0 9.3 I 34 20.1 10.1 2 1 138.3 2.4 2 2 342.3 5.8 2 3 124.0 2.8 2 4 251.9 4.0 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -4 2 -42 -42 -42 -42 -42 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 5 296.0 4.2 6 129.7 2.2 7 292.0 4.3 8 201.1 2.8 9 154.9 10 345.9 4.6 11 242.2 3.4 12 709.2 10.7 13 482.6 7.2 14 174.5 3.6 15 353.3 16 483.0 7.6 17 154.7 4.4 18 259.6 4.3 19 718.9 10.9 20 242.6 4.6 21 72.8 6.4 22 284.8 5.6 23 273.6 4.2 24 164.0 3:'8 25 65.4 6.9 26 129.1 4.3 27 110.4 5.7 28 199.3 29 71.5 13.7 30 42.3 14.9 31 142.8 6.6 32 140.5 33 132.6 7.2 34 162.8 6.8 1 133.0 2.6 2 486.6 7.3 3 579.6 9.6 4 321.8 5.2 5 580.9 8.6.

6 729.6 10.5 7 81.7 2.4 8 218.0- 3.2 9 207.8 3.7 10 105.8 2.7 11 303.3 4.4 12 342.1 4.8 13 282.5 4.1 14 373.1 5.1 15 302.2 4.3 16 266.3 5.7 17 16.6 8.3 18 308.8 19 644.5 9.2 20 305.2 4.7 21 101.5 22 145.4 4.2 23 101.0 24 207.5 25 47.2 9.7 26 290.3 4.8 127 88.5 9.4 128 224.5 4.1 130 185.6 5.1 131 119.2 132 141.7 5.2 133 129.3 6.9 3 34 130.9 7.9 4 1 289.3 4.4 4 2 218.2 3.2 4 3 59.2 2.9 4 4 759.2 4 5 396.0 6.3 4 6 242.3 3.6 4 7 290.6 4.3 4 8 319.6 4.3 4 9 136.8 2.4 SUBSTITIUTE SHEET (RULe. 26) WO 99/10379 WO 9910379PCT/GB98/02542 604.7 9.5 279.9 4.7 240.3 3.4 190.1 3.3 124.3 3.0 438.1 6.5 357.3 5.4 576.1 7.7 170.0 3.5 229.4 4.0 533.9 8.3 375.7 5.4 228.3 4.0 258.3 4.1 44.1 11.2 79.9 6.4 301.2 5.3 214.5 4.2 204.5 4.2 151.5 6.4 27.9 12.3 30.7 12.6 93.9 7.2 174.0 5.8 98.0 7.3 175.7 3.1 301.1 4.3 88.3 2.0 146.2 2.6 204.1 2.8 201.2 3.0 161.1 2.4 575.9 8.1 457.3 6.3 316.7 4.1 340.9 4.8 254.9 4.7 247.9 3.8 402.9 6.5 486.7 6.7 459.1 6.0 420.8 5.9 404.1 5.9 651.0 10.7 285.5 4.5 21.8 10.6 171.0 3.7 163.9 3.6 122.2 4.3 275.1 4.2 184.7 4.2 228.9 4.2 334.1 4.9 195.0 7.3 99.3 6.7 161.3 4.9 225.9 4.9 107.1 7.9 219.0 3.2 224.8 3.5 58.5 2.5 635.9 10.5 311.4 4.8 254.1 3.5 692.2 9.3 484.4 7.1 243.2 3.2 174.3 3.3 141.6 2.6 371.5 5.2 166.4 3.0 585.9 8.5 301.8 4.5 65.8 6.1 944.0 11.8 560.2 8.7 383.3 6.0 274.1 4.9 257.1 4.4 150.6 4.4 197.7 4.0 19.2 9.2 454.1 6.6 134.7 4.3 262.6 5.0 243.2 4.2 296.4 8.7 179.6 4.5 103.8 7.9 202.0 5.9 170.6 5.2 472.5 6.9 547.6 7.8 335.6 5.0 412.5 5.4 84.0 2.1 408.9 6.1 442.6 7.0 272.7 4.3 290.4 4.6 558.5 8.5 1045.8 18.4 453.5 6.9 630.5 8.0 685.1 9.0 17.4 8.8 48.7 7.5 493.4 6.7 418.7 6.7 151.0 3.8 375.3 5.4 66.3 7.2 314.0 5.6 252.7 4.3 260.7 4.2 106.2' 4. 3 133.3 4.9 318.0 4.6 104.1 6.4 380.6 9.3 134.9 5.3 154.7 4.8 163.0 4.7 137.7 6.1 113.9 2.3 13.9 5.5 359.4 5.1 147.8 2.4 200.7 3.0 144.5 2.2 122.9 2.4 293.9 3.8 375.8 5.5 325.6 4.0 385.5 5.9 658.3 9.2 312.9 4.1 142.5 2.8 288.9 5.2 i212.1 4.1 248.2 4.1 324.8 5.5 304.9 4.2 119.5 3.5 306.2 4.8 287.3 5.6 325.9 5.0 122.8 3.8 404.0 6.2 94.9 4.5 216.0 4.1 68.1 8.1 213.1 12.4 103.6 6.4 33.1 13.7 77.9 8.5 149.0 5.2 309.2 4.9 315.1 4.3 440.0 5.3 380.3 5.1 146.7 2.1 37.8 3.2 151.5 2.4 392.9 6.1 680.4 9.5 518.7 7.7 216.2 3.0 370.6 4.9 208.7 3.4 442.2 6.4 496.6 7.8 213.9 4.8 351.9 5.7 614.9 8.7 365.0 5.7 204.2 3.7 106.0 4.9 294.8 4.6 271.5 4.6 197.4 3.9 236.9 3.9 196.7 3.8 91.9 5.1 94.1 5.8 139.1 5.2 87.6 8.0 44.2 14.3 140.8 5.9 147.7 2.2 726.8 10.7 1108.7 1.9 1302.4 4.1 i195.9 3.1 i361.1 4.9 314.8 4.5 1788.5 10.9 484.2 7.3 0 200.6 3.0 1 920.3 12.7 2 579.1 8.8 3 494.0 7.4 4 208.1 4.0 5 244.1 3.8 6 478.1 6.8 7 267.7 4.1 8 256.9 4.1 9 36.8 10.7 .0 133.9 3.9 1 427.4 6.0 :2 161.2 4.5 :3 93.3 6.7 4 270.2 4.3 !5 120.6 5.1 !6 15.1 7.5 t7 20.6 9.6 30.6 12.1 189.3 4.4 289.5 4.8 133.8 4.6 242.1 4.8 28.4 13.3 460.4 8.7 218.5 2.8 160.4 271.8 3.6 138.2 2.1 161.9 2.4 435.0 6.1 109.3 2.2 439.5 6.1 627.6 9.1 450.5 7.2 497.9 7.2 680.1 8.7 623.9 9.1 464.9 6.9 665.5 8.7 327.1 5.8 185.0 3.6 440.6 383.4 6.7 69.6 6.7 54.2 330.0 5.7 72.4 5.9 206.2 3.9 248.9 231.8 4.8 45.6 19.7 117.6 271.6 4.9 82.9 8.3 123.9 5.8 194.1 633.1 17.7 249.8 3.1 214.2 2.8 193.1 2.8 161.1 2.4 598.7 7.7 746.3 10.6 404.7 5.1 707.4 I797.1 10.4 263.4 358.5 4.7 480.0 7.3 1357.2 5.1 i250.9 3.9 293.8 4.7 200.0 3.6 175.4 3.4 70.0 6.8 131.4 213.9 3.6 263.0 4.4 239.1 3.8 1 118.0 4.9 5 66.2 6.7 5 145.3 7 222.3 4.6 3 434.4 8.3 )37.4 13.9 )90.1 6.8 1262.3 5.1 2 124.6 6.4 58.8 2.9 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -91- 246.7 310.0 351.1 525.8 694.9 403.8 670.2 732.4 553.8 425.6 220.3 184.8 219.6 506.7 524.4 255.7 304.1 38.9 72.7 215.9 16.5 305.0 131.7 306.3 233.2 130.8 139.1 220.5 130.9 181.7 168.4 713.8 245.5 688.9 274.2 478.7 738.0 65.3 341.7 424.1 245.8 691.3 516.6 219.6 299.9 333.6 265.6 231.1 197.6 108.5 42.5 114.0 80.2 55.9 141.5 350.8 429.0 75.3 66.5 251.7 184.3 123.1 78.2 233.7 251.0 576.3 518.2 490.6 582.4 685.4 559.6 834.8 3.3 4.0 5.6 8.4 9.8 6.1 13.1 10.2 7.9 5.8 3.1 4.3 8.5 7.7 4.2 4.6 10.8 7.3 4.4 8.0 4.6 4.3 4.7 4.9 4.6 6.3 4.6 5.2 5.1 5.5 15.2 3.5 9.7 4.0 6.9 10.2 2.5 4.8 5.6 3.4 8.9 6.6 3.5 4.1 5.1 4.2 3.8 4.0 3.8 9.0 3.9 5.5 7.9 3.8 4.9 6.1 9.2 9.1 5.0 4.4 6.3 8.9 6.2 4.9 7.9 6.9 6.9 8.2 9.3 6.6 12.5 451.5 7.9 313.4 4.6 578.9 7.5 227.4 3.7 456.8 6.6 289.3 4.4 309.7 4.4 280.9 4.1 81.2 4.5 220.7 4.1 89.1 5.2 21.9 10.2 213.2 5.3 53.3 11.2 179.6 3.6 31.6 11.3 146.3 4.1 312.1 8.6 33.0 12.3 68.5 7.7 75.9 8.8 55.5 11.4 417.7 7.6 355.3 5.0 597.8 7.7 611.5 8.4 715.6 10.4 701.0 9.2 134.9 2.3 295.6 3.7 413.6 5.5 428.3 5.3 190.5 3.6 156.3 3.8 73.7 4.3 614.0 10.7 536.8 7.7 398.5 5.8 269.8 4.2 451.5 7.4 88.7 4.5 284.4 4.7 93.8 5.4 171.6 4.3 366.7 5.3 50.5 9.6 79.2 7.5 52.1 11.8 131.1 6.2 74.9 9.3 69.6 9.7 114.8 7.0 93.2 6.4 216.1 3.7 144.9 2.6 368.9 4.6 600.9 8.0 453.0 6.1 447.2 6.4 702.3 8.5 341.3 5.0 888.9 11.5 475.5 6.7 591.2 7.9 71.4 3.6 278.1 4.6 335.4 4.8 396.1 6.0 181.5 3.1 238.1 4.4 330.0 5.2 I62.5 6.3 507.7 8.4 221.5 3.8 304.2 5.4 98.2 4.4 145.2 3.6 84.8 7.1 266.8 6.9 230.9 4.3 198.0 5.0 20.3 10.1 137.9 5.7 352.9 6.0 334.9 6.7 847.0 14.9 387.3 4.7 288.4 4.6 699.7 8.7 549.7 8.3 192.9 3.4 108.2 2.5 415.9 5.7 682.5 10.3 179.4 3.2 138.3 3.2 413.6 5.3 122.0 2.8 137.3 3.2 231.9 3.8 198.6 3.5 120.6 3.3 163.3 3.5 57.2 7.1 88.2 5.1 318.3 4.8 133.5 5.1 59.0 8.6- 174.1 4.0 112.8 11.3 109.6 6.2 100.0 5.8 193.1 4.8 50.0 13.9 497.0 11.4 581.4 8.9 627.1 8.7 246.6 3.4 567.7 7.5 411.3 5.6 291.2 4.0 348.9 5.0 280.3 4.4 P146.0 2.8 509.6 6.9 463.0 6.5 217.9 3.4 318.3 4.5 202.7 3.5 130.6 3.2 129.7 3.0 205.9 4.8 P106.3 3.8 150.9 3.5 178.2 3.9 181.8 3.7 1151.6 3.7 1 73.7 6.9 i22.4 10.9 i158.0 4.9 1 159.6 4.0 38.5 13.5 )327.2 5.6 40.7 16.2 1 425.8 2 262.2 3 797.3 12.7 4 480.3 6.4 5 587.1 7.9 6 484.9 6.6 7 481.3 6.7 8 668.5 11.6 9 518.7 7.7 10 214.1 3.3 11 412.4 5.4 12 199.1 3.2 13 59.8 4.7 14 251.3 3.9 15 75.6 4.6 16 163.1 3.8 17 200.1 3.4 18 313.6 19 162.0 3.1 20 210.1 4.1 21 215.6 3.7 22 124.5 3.8 23 172.7 3.6 24 289.9 4.9 25 236.6 8.3 26 95.7 6.4 27 88.5 6.7 28 153.6 4.2 29 190.2 4.4 30 61.1 14.8 1 333.4 6.7 2 11.7 5.8 3 437.9 5.9 4 382.6 5 591.0 8.3 6-28-1.2 3.7 7 508.3 6.9 8 143.1 2.4 9 404.7 5.9 10 440.0 6.4 11 148.0 2.7 12 206.7 3.3 13 528.9 8.6 14 265.3 15 316.4 4.4 16 271.4 17 354.6 5.4 18 31.7 10.0 19 125.2 3.8 20 120.7 3.3 21 65.5 6.1 22 202.4 23 231.1 3.9 24 346.3 7.2 25 220.7 4.2 26 91.5 5.8 27 109.6 5.3 28 44.3 12.9 29 138.1 4.8 1 288.0 2 222.2 5.6 3 432.4 5.6 4 335.8 4.6 5 428.7 5.8 6 469.3 6.6 7 536.6 7.8 8 174.3 9 595.3 10 391.9 6.4 11 231.4 3.4 12 211.5 3.7 13 62.3 4.2 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 301.7 124.1 409.2 60.4 18.0 421.9 148.7 60.6 136.5 159.7 37.9 110.0 48.6 94.2 137.8 30.0 147.3 314.0 476.2 700.5 229.2 396.8 520.7 376.2 468.0 332.7 315.6 298.5 308.2 162.7 41.3 187.8 100.0 74.8 152.9 116.5 55.0 213.2 233.6 41.8 39.8 69.9 57.5 19.1 282.8 274.2 26.2 371.7 148.0 520.6 169.4 516.8 172.2 82.3 644.3 369.5 547.8 300.1 518.7 376.6 169.7 185.1 242.8 232.5 176.7 103.0 108.7 209.2 249.4 189.8 51.1 214.0 4.3 3.2 5.7 5.1 8.4 6.1 3.9 5.7 3.5 3.9 16.5 5.2 12.4 6.3 6.0 12.8 3.7 6.1 7.3 9.4 3.5 6.0 7.4 5.0 6.5 4.6 4.5 4.7 4.3 3.3 8.2 3.2 5.3 3.9 3.3 3.4 8.4 4.0 9.8 10.7 11.3 7.6 14.7 9.6 5.2 6.3 7.0 5.0 2.5 7.0 2.6 7.1 2.8 4.1 11.1 4.7 7.9 6.0 8.1 5.1 3.3 3.2 4.1 4.0 3.4 8.7 5.2 4.1 4.4 5.2 11.3 5.1 25 1 25 2 25 3 25 4 25 5 25 6 25 7 25 8 25 9 25 10 25 11 25 12 25 13 25 14 25 15 25 16 25 17 25 18 25 19 25 20 25 21 25 22 25 23 25 24 25 25 25 26 25 27 26 1 26 2 26 3 26 4 26 5 26 6 26 7 26 8 26 9 26 10 26 11 26 12 26 13 26 14 26 15 26 16 26 17 26 18 26 19 26 20 26 21 26 22 26 23 26 24 26 25 26 26 26 27 27 1 27 2 27 3 27 4 27 5 27 6 27 7 27 8 27 9 27 10 27 11 27 12 27 13 27 14 27 15 27 16 27 17 27 18 418.4 59.7 366.4 204.3 199.2 179.5 127.8 199.2 478.6 176.7 260.9 304.9 11.0 129.9 128.3 81.9 285.1 195.5 118.9 186.9 60.3 214.1 200.7 131.7 110.1 41.5 220.1 267.1 85.0 184.9 238.7 472.4 199.7 200.3 155.3 155.8 80.2 44.8 186.0 192.4 170.6 43.2 93.2 110.0 261.8 138.9 125.9 261.4 105.1 48.4 205.6 158.1 147.8 275.9 294.8 389.6 117.7 266.9 167.4 225.3 329.0 109.8 101.4 I361.0 59.1 57.9 370.2 97.3 386.5 135.6 292.9 166.1 8.7 3.5 5.9 3.0 3.4 2.7 2.8 2.9 7.1 2.7 3.9 4.2 5.5 2.7 2.9 4.1 3.7 3.2 3.7 4.1 8.3 4.6 3.9 4.3 5.2 12.9 4.5 5.4 2.8 3.0 3.3 6.2 2.7 2.8 3.5 2.4 3.1 4.8 3.2 3.2 2.9 6.2 3.5 3.5 4.2 3.0 3.5 6.0 4.7 10.0 4.2 3.9 4.7 6.9 5.6 6.3 3.0 3.9 2.5 3.2 4.3 2.3 2.5 4.9 4.1 4.1 5.9 3.8 6.7 3.0 4.5 3.6 -4 27 -4 27 -4 27 -4 27 -4 27 -4 27 -4 27 -4 27 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -4 28 -428 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -4 29 -429 -4 29 -4 29 -429 -4 29 -4 30 -4 30 *430 -4 30 -4 30 -430 -4 30 -4 30 -430 -4 30 -4 30 -4 30 -4 30 -4 30 -4 30 163.2 3.9 368.9 8.5 353.6 6.3 258.7 4.6 58.2 8.4 160.0 3.8 175.4 4.7 184.6 4.1 217.0 6.7.

40.4 4.8 83.0 4.9 261.2 4.1 215.4 3.1 423.6 5.3 161.8 2.3 202.8 2.8 109.3 2.3 256.3 3.9 294.9 4.1 167.7 2.7 88.3 3.8 187.7 3.0 265.2 4.8 162.2 3.1 128.4 3.2 79.9 4.6 232.9 6.5 156.3 3.9 304.2 4.6 219.7 4.6 45.5 10.4 100.7 6.7 20.1 9.2 213.3 6.5 313.7 5.4 291.3 5.9 445.9 6.7 161.4 2.2 192.4 2.8 71.8 2.3 184.9 2.6 43.5 4.6 166.4 3.0 126.0 2.3 *127.2 2.7 90.7 3.8 *42.9 6.2 153.2 3.4 192.0 3.5 186.5 3.2 258.6 6.7 220.1 4.2 I292.3 6.0 65.0 6.1 4 5.9 10.6 1120.1 5.0 171.5 4.0 270.7 6.3 145.7 2.9 118.1 4.8 242.7 4.0 263.0 3.7 146.5 2.2 57.7 3.4 126.7 2.7 332.2 4.8 131.7 2.3 1 144.4 2.8 114.4 2.5 1122.4 2.7 1 49.6 5.8 5 104.8 3.7 149.9 4.3 229.8 6.6 165.8 3.9 127.8 3.7 181.4 3.6 113.2 4.1 231.1 4.3 17.4 8.6 234.8 4.9 82.0 4.1 119.1 4.2 343.8 8.9 78.0 2.8 197.3 3.7 281.3 202.2 3.2 123.4 181.3 2.6 71.7 103.5 2.6 192.3 3.2 213.1 240.7 138.0 3.9 204.2 5.8 101.1 4.1 45.5 8.4 99.2 4.3 119.5 4.9 307.2 174.4 3.7 76.7 5.7 91.4 3.6 303.5 6.7 66.2 4.9 168.5 3.3 67.2 2.3 108.0 204.0 286.8 4.1 214.5 3.2 180.2 2.9 106.7 2.8 16.6 7.3 13.8 6.6 116.6 12.7 21.0 8.6 202.4 89.4 4.3 97.0 65.8 209.7 4.1 183.8 179.4 4.3 110.7 3.9 187.0 95.2 4.3 249.1 6.3 113.8 204.2 3.3 69.3 2.4 219.9 2.9 144.5 2.7 105.1 2.4 207.0 3.3 55.0 6.1 1157.3 6.9 t 95.1 3.7 5 76.0 7.1 5 80.5 7 17.7 8.7 3 136.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -93- -4 33 19 139.1 3.8 -4 33 20 163.7 4.2 -4 33 21 83.6 7.2 -4 34 1 282.9 7.8 -4 34 2 152.2 5.8 -4 34 3 181.3 5.8 -4 34 4 424.4 11.9 -4 34 5 248.2 4.5 -4 34 6 203.7 3.7 -4 34 7 164.7 2.3 -4 34 8 62.7 2.9 -4 34 9 58.3 3.6 -4 34 10 132.2 3.1 -4 34 11 192.3 7.1 -4 34 12 177.6 3.9' -4 34 13 78.0 3.5 -4 34 14 231.3 3.9 -4 34 15 56.6 5.7 -4 34 16 69.7 4.2 -4 34 17 96.7 4.8 -4 34 18 24.1 9.4 -4 34 19 214.4 3.9 -4 34 20 36.8 10.2 -4 35 2 129.8 4.4 -4 35 3 111.6 3.7 -4 35 4 256.0 6.5 -4 35 5 243.9 6.2 -4 35 6 148.5 3.1 -4 35 7 219.5 4.2 -4 35 8 110.2 7.4 -4 35 9 185.5 5.3 -4 35 10 120.7 2.8 -4 35 11 189.8 3.2 -4 35 12 110.8 2.8 -4 35 13 44.0- 6.0- -4 35 14 50.3 5.5 -4 35 15 127.3 2.9 -4 35 16 173.7 3.2 -4 35 17 156.2 3.2 -4 35 18 88.7 5.3 -4 35 19 30.6 11.2 -4 36 1 25.9 9.2 -4 36 2 83.9 4.2 -4 36 3 5.4 2.1 -4 36 5 132.5 6.6 -4 36 6 195.9 5.7 -4 36 7 145.4 3.0 -4 36 8 141.1 2.8 -4 36 9 83.5 2.5 -4 36 10 157.0 3.4 -4 36 11 154.3 2.9 -4 36 12 159.5 2.9 -4 36 13 226.9 3.9 -4 36 14 239.1 3.8 -4 36 15 214.0 3.3 -4 36 16 60.1 5.7 -4 36 17 89.2 4.1 -4 36 18 46.0 11.6 437 5 62.8 6.5 -4 37 6 159.7 4.8 -4 37 7 144.8 2.6 -4 37 8 164.3 2.6 -4 37 9 215.5 3.3 -4 37 10 79.7 2.9 -4 37 11 99.4 2.8 -4 37 12 37.4 7.6 -4 37 13 21.1 9.3 -4 37 14 74.0 3.6 -4 37 15 77.7 3.8 -4 37 16 121.4 3.4 -4 38 4 64.1 4.7 -4 38 6 58.7 6.7 -4 38 7 142.6 2.8 -4 38 8 16.9 6.9 -4 38 9 124.4 2.4 -4 38 10 79.3 3.3 -4 38 11 46.6 4.2 -4 38 12 29.9 8.9 -4 38 13 180.5 3.0 -4 38 14 305.4 4.1 -4 38 15 245.1 6.3 -4 39 5 117.4 4.6 -4 39 6 86.0 5.0 -4 39 7 70.6 3.7 -4 39 8 143.2 2.9 -4 39 9 76.3 2.8 -4 39 10 105.2 2.7 -4 39 11 27.6 8.3 -4 39 12 199.4 3.9 -4 39 13 97.9 4.5 -4 40 6- 122.3 5.1 -4 40 7 60.0 4.3 -4 40 8 184.8 4.2 -4 40 9 144.9 2.5 -4 40 10 114.2 2.3 -4 40 11 166.0 4.9 -4 41 7 135.6 5.4 -4 41 8 126.8 4.5 -3 0 1 203.7 4.9 -3 0 2 270.8 7.8 -3 0 3 340.3 8.0 -3 0 4 62.6 3.4 -3 0 5 732.8 14.9 -3 0 6 346.7 6.2 -3 0 7 311.9 7.3 -3 0 8 114.8 3.1 -3 0 9 209.8 4.0 -3 0 10 244.2 5.1 -3 0 11 494.6 10.6 -3 0 12 67.7 4.8 -3 0 13 311.4 5.9 -3 0 14 179.1 4.3 -3 0 15 228.4 4.4 -3 0 16 438.7 9.5 -3 0 17 572.3 11.6 0 18 374.1 7.9 -3 0 19 415.8 8.1 -3 0 20 349.3 8.4 -3 0 21 62.3 11.8 -3 0 22 310.2 7.3 -3 0 23 141.5 7.1 -3 0 24 49.2 18.3 -3 0 25 27.3 17.0 -3 0 26 42:3 18.9 -3 0 27 135.7 6.7 -3 0 28 248.8 5.9 -3 0 29 77.8 13.7 -3 0 30 170.6 20.9 -3 0 31 121.3 9.5 -3 0 32 159.0 14.4 -3 0 33 66.0 16.5 -3 0 34 14.2 10.5 -3 1 1 394.7 7.3 -3 1 2 283.9 5.5 -3 1 3 632.5 14.5 -3 1 4 149.5 2.8 -3 1 5 393.6 5.9 -3 1 6 207.4 2.8 -3 1 7 229.2 3.5 -3 1 8 405.8 6.3 -3 1 9 109.0 2.6 -3 1 10 272.0 3.9 -3 1 11 318.8 5.5 -3 1 12 107.6 2.7 1 13 147.0 2.6 1 14 402.1 5.5 1 15 351.8 4.5 1 16 188.6 3.3 1 17 314.8 5.2 1 18 254.3 5.1 1 19 449.1 6.3 1 20 365.1 6.1 1 21 603.6 9.6 1 22 230.3 4.3 1 23 191.6 4.5 1 24 117.3 5.3 1 25 402.1 5.4 1 26 92.5 6.3 1 27 143.4 4.5 1 28 180.0 4.3 1 29 275.0 4.1 1 30 37.7 17.0 1 31 55.0 12.7 1 32 64.7 15.4 1 33 97.8 6.6 1 34 20.3 10.0 2 1 51.3 2.8 2 2 33.5 4.8 2 3 274.1 4.8 2 4 146.8 2.9 2 5 902.5 15.1 2 6 617.6 9.5 2 7 738.7 10.0 2 8 211.0 3.2 2 9 359.2 4.8 2 10 326.8 5.2 2 11 248.5 3.8 2 12 276.7 4.1 2 13 183.2 3.0 2 14 754.1 10.8 2 15 323.2 4.5 2 16 402.5 6.1 2 17 354.7 5.6 2 18 510.0 7.2 2 19 784.9 11.0 2 20 42.6 13.1 2 21 108.0 5.2 2 22 159.7 4.7 2 23 405.8 5.6 2 24 188.8 3.9 2 25 263.6 4.4 2 26 140.1 5.9 2 27 290.0 4.6 2 28 67.8 10.2 2 29 117.5 6.2 2 30 181.9 9.3 2 31 190.5 5.0 2 32 121.8 6.6 2 33 127.6 5.4 2 34 253.0 5.4 3 1 212.3 3.4 3 2 337.3 5.0 3 3 225.6 2.9 3 4 507.9 10.3 3 5 673.2 13.0 3 6 361.2 5.4 3 7 479.1 7.5 3 8 265.2 4.0 3 9 508.8 7.4 3 10 226.4 3.5 3 11 136.1 3.5 3 12 507.6 7.3 3 13 572.0 7.6 3 14 262.6 3.9 3 15 445.2 6.2 3 16 406.0 6.3 3 17 634.6 3 18 779.4 13.0 3 19 392.2 5.8 3 20 314.2 5.1 3 21 107.0 3 22. 109.0 5.2 3 23 141.3 4.6 3 24 205.0 3.8 3 25 265.7 4.6 3 26 112.6 3 27 214.0 3.8 3 28 232.7 4.1 3 29 44.7 14.4 3 31 159.4 5.2 3 32 52.0 13.6 3 33 74.6 8.8 3 34 55.2 15.4 4 1 754.6 24.0 4 2 419.5 4 3 507.7 9.4 4 4 508.3 9.1 4 5 648.6 9.3 4 6 550.2 4 7 399.5 5.8 4 8 171.4 2.9 4 9 65.9 3.3 4 10 207.2 3.3 4 11 655.6 9.8 4 12 216.6 3.4 4 13 286.2 4 14 572.5 7.4 4 15 647.8 9.3 4 16 481.2 6.7 4 17 47.3 7.8 4 18 748.8 10.6 4 19 755.6 10.7 4 20 123.9 4 21 191.1 3.8 4 22 204.0 4.1 4 23 107.8 4.6 4 24 246.1 4.4 4 25 319.0 4 26 182.7 4.1 4 27 223.3 3.9 4 28 161.9 4.4 4 29 316.4 7.6 4 30 185.1 5.8 4 31 192.5 5.6 4 32 93.2 4 33 260.4 4 34 58.4 12.2 5 1 404.5 7.2 5 2 415.6 5 3 491.0 5 4 439.9 6.8 5 5 144.0 2.6 5 6 402.8 5.9 5 7 634.1 7.9 5 8 273.6 4.1 5 9 600.4 8.8 5 10 463.1 6.3 5 11 84.9 3.1 5 12 409.3 5 13 795.9 11.5 5 14 341.3 4.8 5 15 890.3 11.8 5 16 360.4 5.9 5 17 243.2 4.1 5 18 542.7 7.2 5 19 175.0 4.2 5 20 264.1 4.9 5 21 357.9 5.9 SUBSTITUTE SHEET (RULE 2B) WO 99/10379 WO 9910379PCT/GB98/02542 -94- -3 5 22 242.3 4.9 -3 7 27 74.1 7.2 -3 10 1 177.7 2.5 -3 12 7 145.2 2.8 -3 5 23 164.4 4.0 -3 7 28 100.1 7.3 -3 10 2 215.1 3.1 -3 12 8 491.1 7.2 -3 5 24 119.2 4.5 -3 7 29 22.8 11.3 -3 10 3 300.4 4.2 -31 12 9 234.2 3.4 -3 5 25 80.8 5.8 -3 7 30 103.0 6.0 -3 10 4 502.0 6.8 -3 12 10 776.9 10.2 -3 5 26 115.1 4.6 -3 7 31 137.7 4.8 -3 10 5 342.9 4.5 -3 12 11 358.8 5.2 -3 5 27 129.6 4.3 -3 7 32 207.0 4.8 -3 10 6 592.7 8.4 -3 12 12 873.0 12.4 -3 5 28 244.0 4.2 -3 7 33 65.0 10.7 -3 10 7 278.8 3.8 -3 12 13 273.2 4.1 -3 5 29 194.5 4.3 -3 8 1 677.9 9.9 -3 10 8 859.8 13.2 -3 12 14 126.3 5.2 -3 5 30 224.4 4.9 -3 8 2 429.4 5.8 -3 10 9 758.7 10.6 -3 12 15 349.0 6.3 -3 5 31 117.6 5.9 -3 8 3 348.9 5.5 -3 10 10 333.9 4.6 -3 12 16 199.9 3.4 -3 5 32 121.5 5.6 -3 8 4 500.0 6.9 -3 10 11 615.5 8.8 -3 12 17 137.8 4.2 -3 5 33 150.1 5.1 -3 8 5 368.8 4.8 -3 10 12 119.5 3.2 -3 12 18 338.2 4.7 -3 5 34 20.2 10.0 -3 8 6 544.2 8.4 -3 10 13 88.2 3.2 -3 12 19 340.4 5.2 -3 6 1 207.9 3.6 -3 8 7 384.4 6.1 -3 10 14 107.2 3.6 -3 12 20 128.0 6.7 -3 6 2 306.5 5.3 -3 8 8 238.0 4.4 -3 10 15 284.6 4.6 -3 12 21 307.5 5.2 -3 6 3 173.9 2.6 -3 8 9 212.0 3.3 -3 10 16 522.4 7.6 -3 12 22 21.1 9.2 -3 6 4 728.1 11.6 -3 8 10 688.1 10.8 -3 10 17 256.5 5.2 -3 12 23 296.7 -3 .6 5 48.9 3.7 -3 8 11 209.4 3.1 -3 10 18 250.4 5.3 -3 12 24 104.2 -3 6 6 78.9 2.1 -3 8 12 289.0 3.9 -3 10 19 182.3 4.7 -3 12 25 198.9 3.7 -3 6 7 448.9 7.1 -3 8 13 161.6 2.7 -3 10 20 423.6 6.9 -3 12 26 51.3 7.6 -3 6 8 198.9 2.7 -3 8 14 240.2 3.8 -3 10 21 151.9 4.2 -3 12 27 146.1 3.9 -3 6 9 672.4 9.2 -3 8 15 428.1 6.4 -3 10 22 333.9 4.8 -3 12 28 283.0 20.9 -3 6 10 245.4 3.8 -3 8 16 224.5" 4.5 -3 10 23 108.3 4.0 -3 12 29 134.9 6.3 -3 6 11 188.7 3.3 -3 8 17 158.4 4.3 -3 10 24 161.9 3.5 -312 30 80.3 9.1 -3 6 12 333.6 4.7 -3 8 18 180.7 3.6 -3 10 25 118.7 3.9 -3 12 31 232.1 4.9 -313 8. -3 8 19 294.6 5.6 -3 10 26 168.6 3.9 -3 12 32 106.2 7.1 -3 6 14 583.6 8.0 -3 8 20 206.3 4.4- -3 10 27 121.4 4.7 -3 13 1 614.7 12.9 -3 6 15 1008.1 12.5 -3 8 21 169.7 4.1 -3 10 28 179.9 5.8 -3 13 2 393.4 5.9 -3 6 16 385.4 6.3 -3 8 22 152.9 3.7 -3 10 29 24.1 11.4 -3 13 3 413.7 5.3 -3 6 17 765.4 12.1 -3 8 23 409.7 6.9 -3 10 30 267.7 4.7 -3 13 4 493.4 6.6 -3 6 18 57.5 8.7 -3 8 24 182.0 4.7 -3 10 31 65.4 8.3 -3 13 5 609.7 7.3 -3 6 19 59.0 8.6 -3 8 25 68.4 8.4 -3 10 32 27.1 12.7 -3 13 6 69.0 2.6 -3 6 20 178.3* 3.7 -3 8 26 162.2 4.2 -3 10 33 254.7 5.2 -3 13 7 314.6 4.7 -3 6 21 478.0 7.5 -3 8 27 211.0 3.9 -3 11 1 429.6 6.6 -3 13 8 68.5 3.1 -3 6 22 304.5 4.5 -3 8 28 218.4 4.2 -3 11 2 341.1 5.9 -3 13 9 266.5 3.4 -3 6 23 23.2 10.9 -3 8 29 367.6 14.7 -3 11 3 351.7 5.4 -3 13 10 406.0 6.3 -3 6 24 148.8 4.4 -3 8 30 152.1 4.7 -3 11 4 106.5 1.9 -3 13 11 185.0 3.1 -3 6 25 219.0 3.9 -3 8 31 106.5 6.5 -3 11 5 62.5 2.2 -3 13 12 384.3 5.9 -3 6 26 181.5 4.0 -3 8 32 149.9 5.4 -3 11 6 196.4 2.9 -3 13 13 53.2 10.5 -3 6 27 159.1 4.1 -3 8 33 146.3 5.2 -3 11 7 249.5 3.6 -3 13 14 371.7 5.1 -3 6 28 228.6 4.6 -3 9 2 476.7 6.6 -3 11 8 262.2 3.7 -3 13 15 116.9 3.9 -3 6 29 140.3 7.8 -3 9 3 246.7 3.5 -3 11 9 239.9 3.4 -3 13 16 321.4 4.4 -3 6 30 238.0 5.0 -3 9 4 681.0 9.7 -3 11 10 360.8 4.8 -3 13 17 249.2 4.1 -3 6 31 84.4 10.5 -3 9 5 590.6 9.9 -3 11 11 318.2 4.1 -3 13 18 26.3 10.0 -3 6 32 144.4 5.1 -3 9 6 108.4 2.4 -3 11 12 246.6 3.5 -3 13 19 23.6 9.9 -3 6 33 30.2 13.2 -3 9 7 127.9 2.3 -3 11 13 584.5 7.8 -3 13 20 239.4 3.8 -3 6 34 141.2 5.6 -3 9 8 446.8 6.6 -3 11 14 526.1 8.4 -3 13 21 *30.3 12.1 -3 7 1 621.5 13.3 -3 9 9 103.9 2.5 -3 11 15 223.5 4.0 -3 13 22 159.3 -3 7 3 403.7 5.3 -3 9 10 549.4 7.6 -3 11 16 649.7 11.1 -3 13 23 180.2 3.6 -3 7 4 276.7 4.2 -3 9 11 282.9 4.0 -3 11 17 363.1 5.5 -3 13 24 148.5 3.7 -3 7 5 210.9 4.2 -3 9 12 263.4 4.0 -3 11 18 255.9 5.9 -3 13 25 121.0 5.2 -3 '7 6 662.6 8.7 -3 9 13 298.8 4.0 -3 11 19 345.1 5.0 -3 13 26 289.6 4.1 -3 7 7 91.8 2.5 -3 9 14 165.7 3.5 -3 11 20 290.7 5.0 -3 13 27 138.0 4.6 -3 7 8 308.3 4.6 -3 9 15 274.7 5.0 -3 11 21 223.1 4.0 -3 13 28 269.2 14.5 -3 7 9 34.9 4.8 -3 9 16 640.9 8.7 -3 11 22 146.3 3.9 -3 13 29 235.4 4.6 -3 7 10 248.3 3.7 -3 9 17 591.7 10.3 -3 11 23 100.2 5.5 -3 13 30 145.9 4.6 -3 7 11 575.8 8.1 -3 9 18 444.5 6.4 -3 11 24 254.7 4.4 -3 13 31 199.9 4.8 -3 7 12 578.5 7.6 -3 9 19 358.1 6.3 -3 11 25 140.0 3.6 -3 13 32 209.8 4.9 -3 7 13 818.1 11.4 -3 9 20 548.8 8.1 -3 11 26 231.5 3.9 -3 14 1 254.6 3.8 -3 7 14 466.4 6.9 -3 9 21 236.6 4.0 -3 11 27 291.2 4.6 -3 14 2 593.1 7.7 -3 7 15 524.6 8.1 -3 9 22 300.8 5.1 -3 11 28 20.6 9.9 -3 14 3 361.4 4.7 -3 7 16 189.4 4.2 -3 9 23 155.7 3.7 -3 11 29 77.0 6.7 -3 14 4 96.9 1.8 -3 7 17 587.6 10.4 -3 9 24 158.0 3.8 -3 11 30 98.4 7.1 -3 14 5 237.5 2.9 -3 7 18 401.5 6.9 -3 9 25 241.2 4.0 -3 11 31 127.1 5.2 -3 14 6 119.8 -3 7 19 399.2 6.2 -3 9 26 223.9 4.0 -3 11 32 158.9 5.0 -3 14 7 320.8 4.4 -3 7 20 51.4 8.2 -3 9 27 213.6 4.7 -3 11 33 177.6 5.5 -3 14 8 486.9 7.2 -3 7 21 57.5 7.0 -3 9 28 89.9 5.7 -3 12 1 357.3 5.1 -3 14 9 405.7 -3 7 22 209.5 5.7 -3 9 29 286.4 12.8 -3 12 2 426.9 6.9 -3 14 10 225.8 2.8 -3 7 23 184.6 5.4 -3 9 30 255.4 4.8 -3 12 3 52.5 2.5 -3 14 11 854.8 11.9 -3 7 24 119.5 7.9 -3 9 31 136.7 6.5 -3 12 4 208.6 3.0 -3 14 12 594.6 -3 7 25 386.7 5.4 3 9 32 32.9 14.8 -3 12 5 453.7 6.3 -3 14 13 336.2 -3 7 26 125.3 4.0 3 9 33 108.7 6.2 -3 12 6 314.7 4.4 -3 14 14 274.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02 542 14 15 14 16 14 17 14 18 14 19 14 20 14 21 14 22 14 23 14 24 14 25 14 26 14 27 14 29 14 30 14 31 14 32 1 2 3 41 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 16 1 16 2 M6 3 16 4 16 5 16 6 16 7 16 8 16 9 16 10 16 11 16 12 16 13 16 14 16 15 16 16 16 17 16 18 16 19 16 20 16 21 16 22 16 23 369.7 628.5 365.9 172.0 42.3 166.4 313.6 78.5 70.1 215.8 125.4 180.5 322.9 30.5 165.7 232.8 141.0 114.8 229.0 178.1 217.8 498.5 363.9 9 13.7 760.8 863.0 843.6 161.0 470.4 149.5 877.7 409.6 250.0 382.7 169.6 168.3 188.5 130.4 202.4 250.9 146.5 310.8 123.4 115.3 178.1 255.2 74.2 162.1 69.3 353.1 290.5 427.9 447.8 176.6 314.9 593.5 309.6 342.2 403.5 152.6 470.3 262.7 515.6 182.9 351.5 341.8 282.8 293.4 316.0 294.8 183.7 64.5 5.3 12.1 6.9 3.7 11.4 3.6 4.8 5.3 6.9 4.1 3.8 3.8 5.2 12.8 4.9 4.9 5.3 2.0 3.1 2.5 2.8 6.5 5.8 14.7 11.1 12.0 12.1 2.8 7.1 4.1 12.0 7.4 4.1 5.7 3.4 3.6 3.5 4.1 3.9 4.3 3.5 5.4 4.9 7.6 4.2 4.6 7.2 4.5 9.4 9.4 4.0 5.7 6.0 2.4 4.6 10.5 4.3 4.7 6.1 4.3 7.3 3.9 10.1 4.2 7.0 5.5 4.4 4.6 4.7 4.7 3.6 7.2 24 38.7 11.1 25 137.4 4.0 26 354.7 5.7 27 221.8 9.2 28 38.3 13.5 29 200.3 4.8 30 134.8 6.3 31 134.9 6.0 1 714.3 14.9 2 692.6 10.3 3 320.3 4.5 4 685.5 9.0 5 392.3 5.1 6 408.9 5.3 7 228.9 3.4 8 441.6 6.2 9 207.3 3.2 10 616.9 9.3 11 306.4 4.2 12 536.9 7.5 13 448.0 7.1 14 432.0 5.7 15 331.6 6.4 16 444.9 6.7 17 120.4 3.4 18 192.6 3.6 19 80.2 4.7 20 339.7 5.2 21 160.8 3.8 22 339.6 5.3 23 123.9 3.9 24 69.5 7.0 25 145.0 3.8 26 209.5 4.3 27 162.0 4.9 28 106.8 6.6 29 141.0 6.2 30 24.1 11.6 31 255.4 5.0 1 365.1 6.9 2 252.9 3.6 3 252.3 3.4 4 630.2 8.8 5 372.0 4.7 6 460.2 7.9 7 984.3 13.9 8 247.9 3.8 9 143.1 2.7 10 439.5 6.3 11 236.2 3.8 12 473.8 10.1 13 550.5 7.6 14 657.9 11.2 15 222.9 4.3 16 299.4 5.1 17 441.9 5.8 18 120.1 4.3 19 202.8 3.6 20 115.8 3.7 21 174.2 3.7 22 159.9 5.4 23 116.4 4.2 24 120.8 4.3 25 35.3 13.0 26 389.4 8.7 27 141.3 4.5 28 106.5 6.2 29 104.1 7.3 30 155.5 4.9 31 51.5 14.0 1 779.7 14.3 2 441.1 9.1 3 332.8 4.6 4 537.0 6.8 5 383.9 5.5 6 589.8 8.1 7 397.0 5.4 8 58.8 3.6 9 835.8 10.6 10 399.9 6.1 11 171.6 3.7 12 391.3 6.4 13 533.9 8.3 14 213.6 3.2 15 220.9 4.2 16 174.5 3.7 17 449.4 6.2 18 249.6 5.0 19 66.8 5.3 20 181.9 3.5 21 199.8 3.6 22 159.9 3.4 23 68.0 7.2 24 212.3 3.9 25 120.1 4.3 26 32.0 14.9 27 96.7 5.8 28 125.6 4.5 29 262.0 5.2 30 28.3 12.0 1 238.6 4.5 2 404.9 7.5 3 153.5 2.5 4 211.7 3.5 5 173.3 3.1 6 123.4 2.3 7 143.7 2.5 8 470.3 6.7 9 769.3 10.2 10 264.2 3.5 11 200.9 3.1 12 471.6 8.3 13 217.4 3.4 14 144.9 3.6 15 251.5 4.8 16 418.6 6.2 17 175.4 3.2 18 152.2 3.3 19 180.4 3.5 20 166.3 3.4 21 257.7 4.2 22 194.6 3.6 23 88.2 6.0 24 234.8 4.5 25 358.9 8.2 26 96.4 5.4 27 272.1 4.6 28 179.3 4.5 29 72.3 7.9 30 19.8 10.0 2 673.9 12.2 3 553.9 7.2 4 550.1 7.3 5 259.3 3.6 6 594.5 7.7 7 215.4 3.4 8 187.9 2.8 9 165.1 2.7 10 469.9 7.6 11 453.8 8.3 12 211.0 3.3 13 321.1 5.0 14 237.6 3.9 15 221.2 3.4 16 207.7 4.3 17 99.5 3.6 18 299.9 4.8 19 191.5 3.4 20 273.5 4.2 21 52.5 8.1 22 324.9 4.8 23 72.6 24 220.2 4.4 25 25.9 11.5 26 222.3 4.4 27 92.4 7.4 28 156.4 4.7 29 88.5 6.8 1 337.9 6.6 2 281.3 6.6 3 435.5 4 558.2 7.6 5 57.8 6 73.9 2.6 7 448.2 8 925.3 12.5 9 752.2 12.8 10 347.4 5.4 11 554.0 8.8 12 305.9 4.1 13 189.1 3.3 14 279.1 4.7 15 217.9 3.4 16 321.1 4.3 17 156.3 3.8 18 123.4 19 222.6 3.6 20 77.7 6.2 21 66.7 5.7 22 179.7 4.4 23 30.7 10.8 24 266.1 8.1 25 145.8 5.2 26 207.4 27 95.1 28 151.3 5.2 29 104.6 6.2 1 382.3 14.2 2 176.7 3.7 3 781.8 15.4 4 512.9 7.1 5 294.3 3.9 6 675.3 11.5 7 209.2 3.1 8 258.4 3.8 9 797.8 12.6 10 633.1 9.4 11 528.6 7.9 12 210.6 3.7 13 98.0 3.8 14 132.9 3.6 15 94.9 3.2 16 254.9 3.9 17 205.1 18 365.2 5.8 19 71.4 5.2 20 24.4 10.0 21 271.4 4.1 22 80.9 7.8 23 166.5 8.3 24 101.2 4.8 25 135.3 26 83.7 6.6 27 74.6 7.3 128 242.4 4.9 1 1 593.6 16.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02S42 226.0 -8.1 339.9 6.4 616.0 9.1 559.6 7.7 68.6 2.9 225.3 3.4 314.2 5.5 202.9 3.6 112.1 3.2 183.7 3.2 600.0 8.8 263.5 3.7 272.4 3. 9 109.8 3.9 32.1 8.7 215.1 3.5 189.5 3.3 286.4 4.3 79.9 6.2 240.7 4.1 104.5 6.6 210.9 5.1 174.8 4.2 109.1 5.2 108.0 5.0 188.8 4.3 92.8 8.5 81.1 4.3 393.3 12.5 158.1 3.0 266.4 3.6 219.1 3.4 256.6 4.7 169.7 3.2 309.8 4.4 10.8 5.3 334.4 4.7 158.0 3.0 194.6 3.3 1 346.8 4.7 1 145.5 2.9 ;91.1 6.0 i67.1 4.7 1 218.0 3.7 3289.6 4.9 52.9 5.9 177.0 3.9 1 131.3 3.7 Z 224.6 10.6 ;147.2 4.4 t 76.9 8.0 226.5 4.4 18.9 9.3 7 118.1 5.2 305.4 8.4 362.9 8.9 339.4 6.5 *288.6 5.5 177.4 2.5 351.5 5.8 121.1 2.3 89.9 2.8 245.4 3.3 0 156.5 2.8 1 198.0 3.0 2 155.5 3.1 3 127.1 3.3 4 114.5 2.9 117.0 2.9 6 140.6 3.0 7 213.1 3.4 8 156.9 3.1 -3 26 19 12.9 6.5 -3 26 20 216.5 3.7 -3 26 21 267.9 6.5 -3 26 22 142.1 4.2 -3 26 23 168.2 3.7 -3 26 24 139.9 4.4 -3 26 25 118.4 5.1 -3 26 26 113.6 5.5 -3 26 27 42.9 14.7 -3 27 1 345.6 7.7 -3 27 2 142.5 4.3 -3 27 3 87.9 4.3 -3 27 4 532.8 8.4 -3 27 5 436.1 6.4 -3 27 6 200.8 2.8 -3 27 7 251.5 3.4 -3 27 8 256.1 3.7 -3 27 9 352.9 5.0 -3 27 10 227.0 3.4 -3 27 11 82.4 3.4 -3 27 12 272.7 4.4 -3 27 13 72.3 3.3 -3 27 14 130.3 2.7 -3 27 15 96.0 3.0 -3 27 16 233.5 3.7 -3 27 18 103.5 3.7 -3 27 19 138.5 4.1 -3 27 20 21.0 10.2 -3 27 21 241.4 4.1 -3 27 22 61.2 7.6 -3 27 23 35.1 11.3 -3 27 24 135.5 3.9 -3 27 25 67.3 6.9 -3 27 26 148.5 4.6 -3 28 2 169.6 4.4 -3 28 3 90.0 4.4 -3 28 4 107.3 2.0 -3 28 5 357.6 6.0 -3 28 6 301.0 4.0 -3 28 7 220.3 3.2 -3 28 8 82.5 2.7 -3 28 9 290.3 4.3 -3 28 10 156.9 2.5 -3 28 11 111.4 2.5 -3 28 12 132.8 2.6 -3 28 13 207.5 3.5 -3 28 14 83.9 4.8 -3 28 15 203.9 3.7 -3 28 16 156.6 3.1 -3 28 17 85.4 3.8 -3 28 18 184.1 3.0 -3 28 19 101.7 5.1 -3 28 20 25.5 11.6 -3 28 21 91.0 4.7 -3 28 22 146.6 4.2 -3 28 23 93.5 5.6 -3 28 24 175.6 3.9 -3 28 25 64.0 8.7 -3 29 2 436.1 12.3 -3 29 3 309.1 8.1 -3 29 4 182.9 3.2 -3 29 5 112.8 2.2 -3 29 6 237.8 3.3 -3 29 7 45.2 3.4 -3 29 8 356.5 4.7 -3 29 9 50.7 3.4 -3 29 10 206.8 3.1 -3 29 11 48.9 5.8 -3 29 12 91.1 3.1 -3 29 13 170.1 2.9 -3 29 14 255.5 4.0 -3 29 15 231.3 3.5 174.7 3.1 296.0 4.5 18.3 8.9 159.8 3.9 130.6 3.7 280.6 4.7 138 .0 4.0 120 .4 3.8 69.5 8.2 71.1 6.7 159.2 4.0 105.0 3.6 141.8 2.7 249.5 3.9 29.8 4.0 261.9 4.2 59.0 2.9 114.5 2.1 103.3 2.4 217.6 3.5 280.7- 4.4 88.9 3.1 157.5 3.1 172.9 3.2 80.5 4.7 238.9 5.0 15.0 7.3 192.1 3.6 320.6 5.3 174.8 4.0 191.6 3.9 43.3 11.9 137.5 4.1 270.9 7.3 124.6 2.7 79.5 1.9 45.5 3.5 58.6 3.1 220.6 3.2 114.8 2.7 121.6 2.4 129.3 2.8 62.3 4.8 101.7 3.0 162.1 3.6 239.7 6.7 189.5 4.2 1149.7 3.3 195.9 3.7 89.2 4.3 190.3 3.8 17.4 8.4 1130.2 4.6 240.3 6.9 147.6 3.2 217.5 4.3 147.7 2.5 72.1 2.4 154.3 3.4 157.9 2.4 1 208.9 3.2 2 63.7 3.7 3 257.6 4.7 4 11.4 5.7 5 196.6 7.2 6 11.2 5.7 7 180.2 3.4 8 138.4 3.9 9 234.4 4.0 0 224.4 3.8 1 20.2 9.5 2 174.3 3.8 179.0 4.8 112.6 2.7 140.6 3.6 124.8 2.1 172.3 2.6 68.3 43.1 323.3 4.9 105.1 2.8 52.8 12.4 140.8 3.6 151.1 2.9 213.5 3.6 282.7 64.7 172.4 3.4 174.0 261.3 4.6 65.6 2.9 184.9 3.3 146.6 3.6 12.0 131.7 2.4 136.9 170.6 220.3 5.3 171.2 3.3 140.3 124.0 3.6 93.9 3.6 113.4 3.9 107.6 3.9 220.0 4.1 102.4 58.8 157.1 3.4 194.2 4.4 101.9 11.6 149.9 22.5 8.3 83.0 3.1 96.4 2.9 64.4 4.4 1-16. *9 3'.1 117.7 3.4 174.5 3.3 29.5 9.7 70.5 11.8 5.9 199.1 8.2 160.3 6.6 196.3 3.7 132.3 2.4 122.5 2.6 1 140.5 2.7 Z 182.4 3 116.2 2.7 4 94.8 3.3 5 145.4 5 230.8 3.8 7 124.3 4.1 9 19.9 32.9 7.4 160.9 3.8 207.5 3.7 100.0 2.9 0 168.5 2.7 1 93.4 2.7 2 102.8 2.8 3 78.2 4 132.9 2.8 5 225.9 3.8 SUBSTITUTE SHEET (RULE -26) WO 99/10379 WO 9910379PCT/GB98/02542 -3 37 16 13.7 6.8 -3 37 17 38.4 11.5 -3 38 6 153.9 5.0 -3 38 7 94.1 3.2 -3 38 8 117.6 3.1 -3 38 9 114.0 2.4 -3 38 10 121.4 2.6 -3 38 11 134.6 2.5 -3 38 12 244.7 3.6 -3 38 13 51.5 4.8 -3 38 14 128.0 3.2 -3 38 15 178.0 3.4 -3 39 7 171.7 5.3 -3 39 8 78.4 3.4 -3 39 9 86.9 3.1 -3 39 10 73.0 2.5 -3 39 11 44.3 4.7 -3 39 12 76.0 3.1 -3 39 13 131.2 3.1 -3 40 7 128.6 3.4 -3 40 8 67.5 3.3 -3 40 9 178.7 3.9 -3 40 10 83.3 3.2 -3 40 11 110.6 2.6 -3 41 8 57.0 3.8 -3 41 9 81.9 4.7 -2 0 3 69.1 2.9 -2 0 4 9.6 6.6 -2 0 5 395.3 9.8 -2 0 6 903.5 22.1 -2 0 7 45.2 4.7 -2 0 8 247.9 4.7 -2 0 9 456.6 10.0 -2 0 10 118.9 3.5 -2 0 11 297.7 5.6 -2 0 12 48.8 6.9 -2 0 13 393.8 7.7 -2 0 14 80.5 4.4 -2 0 15 207.2 4.7 -2 0 16 151.2 4.9 -2 0 17 223.6 13.8 -2 0 18 524.3 10.7 -2 0 19 154.4 5.5 -2 0 20 41.4 17.1 -2 0 21 88.6 8.6 -2 0 22 250.9 7.2 -2 0 23 67.4 20.9 -2 0 24 31.3 16.7 -2 0 25 33.2 17.3 -2 0 26 131.8 6.8 -2 0 27 97.7 7.1 -2 10 28 47.9 14.0 -2 0 29 281.9 6.3 -2 0 30 267.9 14.6 -2 0 31 134.9 8.8 -2 0 32 111.0 8.9 -2 0 33 116.5 8.4 -2 0 34 157.9 13.3 -2 1 3 246.2 4.7 -2 1 4 209.3 4.0 -2 1 5 597.2 9.1 -2 1 6 239.3 3.9 .2 1 7 272.5 4.0 -2 1 8 237.9 3.7 -2 1 9 163.6 2.7 -2 1 10 84.0 2.7 -2 1 11 386.1 4.8 -2 1 12 314.2 4.4 -2 1 13 395.0 5.2 -2 1 14 265.6 4.7 -2 1 15 393.0 5.5 -2 1 16 298.7 4.6 1 17 518.6 7.2 1 18 577.3 9.2 I 19 425.4 6.4 1 20 436.0 6.3 1 21 347.7 5.3 1 22 460.7 6.6 1 23 332.0 4.8 1 24 148.5 4.2 1 25 92.8 5.7 1 26 173.6 3.7 1 27 64.8 6.9 1 28 63.2 6.7 1 29 292.1 4.5 1 30 214.5 19.8 1 31 165.5 6.5 1 32 108.9 5.9 1 33 74.3 9.2 1 34 127.1 7.7 2 2 225.4 5.9 2 3' 350.7 6.5 2 4 153.5 2.9 2 5 251.2 4.6.

2 6 462.1 7.6 2 7 518.1 9.0 2 8 185.9 2.9 2 9 249.2. 3.6 2 10 299.7 4.3 2 11 329.0 5.4 2 12 386.9 5.4 2 13 277.4 3.8 2 14 490.5 10.7 2 15 783.2 10.6 2 16 283.0 4.0 2 17 416.8 7.3 2 18 522.8 8.3 2 19 259.3 4.2 2 20 242.9 4.2 2 21 277.3 5.3 2 22 280.4 4.5 2 24 265.0 4.4 2 25 201.6 4.5 2 26 166.3 4.1 2 27 272.5 4.5 2 28 91.6 6.9 2 29 270.4 4.7 2 30 273.7 13.6 2 31 123.4 6.1 2 32 162.5 4.8 2 33 45.4 12.7 2 34 156.1 6.9 3 2 128.6 2.6 3 3 419.3 7.6 3 4 591.9 9.1 3 5 308.1 5.9 3 6 403.1 7.0 3 7 65.4 3.3 3 8 257.8 4.3 3 9 124.7 2.3 3 10 447.1 6.1 3 11 290.5 4.4 3 12 317.9 4.6 3 13 728.7 9.9 3 14 371.7 8.0 3 15 422.9 5.9 3 16 507.8 8.4 3 17 260.9 4.6 3 18 296.1 6.1 3 19 207.2 4.0 3 20 137.1 4.3 3 21 84.8 5.4 3 22 175.2 3.9 3 23 209.5 5.0 3 24 178.1 3.9 3 25 174.5 4.0 3 26 174.8 3.8 3 27 161.4 3.8 3 28 136.9 4.5 3 29 106.3 7.2 3 30 246.3 12.9 3 31 362.8 5.9 3 32 133.0 5.2 3 33 62.5 9.5 3 34 234.0 4.9 4 1 137.9 2.4 4 2 377.7 6.4 4 3 653.5 12.8 4 4 390.4 7.1 4 5 36.8 3.4 4 6 367.5 6.2 4 7 97.4 2.2 4 8 342.6 4.9 4 9 346.9 5.5 4 10 337.0 4.7 4 11 411.9 6.0 4 12 126.5 2.7 4 13 80.4 4.0 4 14 844.9 13.2 4 15. 304.2 4.5 4 16 340.3 5.6 4 17 322.3 5.3 4 18 365.6 7.0 4 19 358.0 5.6 4 20 208.8 4.1 4 21 281.1 4.3 4 22 19.8 9.3 4 23 190.4 4.0 4- 24 282.7 4.5 4 25 65.3 6.9 4 26 133.5 4.0 4 27 92.7 4.9 4 28 113.6 4.5 4 29 75.6 7.5 4 30 175.7 7.9 4 31 124.7 5.6 4 32 65.6 10.3 4 33 309.5 5.5 4 34 130.7 7.5 5 1 267.1 5.0 5 2 210.2 3.7 5 3 713.1 18.1 5 4 372.4 5.8 5 5 616.1 11.2 5 6 319.1 4.5 5 7 268.5 4.3 5 8 326.2 5.0 5 9 196.6 3.2 5 10 504.6 6.7 5 11 552.2 6.8 5 12 61.7 3.8 5 13 831.6 14.5 5 14 194.6 3.9 5 15 484.7 7.0 5 16 188.0 3.7 5 17 507.0 7.6 5 18 552.7 7.8 5 19 329.3 5.5 5 20 355.8 5.8 5 21 171.5 4.0 5 22 406.2 6.1 5 23 89.6 6.3 5 24 171.1 3.5 5 25 365.2 5.5 5 26 187.0 3.7 5 27 161.2 4.5 5 28 171.3 3.9 5 29 173.3 4.6 5 30 31.6 14.1 5 31 60.3 11.6 5 32 86.1 7.3 5 33 88.5 5 34 31.2 13.8 6 1 124.7 2.4 6 3 615.4 18.4 6 4 159.4 6 5 481.9 8.1 6 6 109.2 6 7 379.0 5.2 6 8 359.6 5.2 6 9 576.8 8.1 6 10 201.9 3.1 6 11 246.5 6 12 73.7 3.7 6 13 196.7 3.9 6 14 391.9 6.9- 6 15 229.3 3.7 6 16 260.0 4.2 6 17 563.3 7.7 6 18 452.3 6.4 6 19 223 .2 4.2 6 20 482.6 6 21 319.1 5.2 6 22 142.6 4.7 6 23 287.8 4.6 6 24 221.0 3.9 6 25 86.1 5.6 6 26 147.4 3.9 6 27 101.5 4.4 6 28 222.8 4.2 6 29 91.1 6 30 109.6 6 31 84.2 6 32 271.1 5.6 6 33 224.9- 4.6 6 34 35.2 14.2 7 1 133.2 2.4 7 2 526.4 7 3 737.3 12.7 7 4 179.9 7 5 354.6 5.3 7 6 244.5 3.6 7 7 371.2 5.8 7 8 380.5 7 9 365.2 5.1 7 10 263.9 7 11 324.6 4.9 7 12 352.2 5.3 7 13 1133.0 24.4 7 14 160.2 3.3 7 15 726.5 10.4 7 16 472.0 7 17 532.7 7.6 7 18 436.8 6.2 7 19 556.2 8.3 7 20 293.0 4.9 7 21 208.6 3.9 7 22 481.7 7.1 7 23 144.3 5.2 7 24 465.4 6.9 17 25 165.0 3.7 1 7 26 174.6 7 27 88.1 5.6 Z7 28 154.5 Z- 7 30 79.4 6.9 2 7 31 61.5 13.9 2 7 32 150.0 5.3 2 7 33 114.2 6.6 SUBSTITUTEI SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 59.9 1.5 86.2 1.5 826.9 17.1 136.5 2.1 73.9 2.1 383.7 5.2 450.1 6.3 527.7 7.4 376.4 5.7 409.5 6.2 348.0 5.1 326.4 4.8 643.8 8.7 656.9 10.8 140.9 3.2 257.5 4.9 253.5 5.5 97.0 4.1 125.2 6.1 557.3 8.0 132.6 3.6 317.6 4.9 337.0 5.1 224.5 3. 9 132.6 4.1 136.0 4.4 204.5 4.2 160.4 3.9 283.9 13.7 122.6 5.1 176.5 5.0 185.0 4.8 148.6 5.4 569.3 7.8 300.2 4.5 115.3 2.1 821.7 12.0 286.8 4.3 303.0 4.8 412.2 6.0 148.9 2.4 574.7 7.9 211.7 3.0 791.7 12.0 160.2 2.9 399.1 6.2 73.8 4.1 431.8 6.0 364.1 5.3 690.4 9.4 250.5 4.4 288.5 6.0 342.8 5.0 329.1 5.1 167.9 3.8 244.2 4.2 163.7 3.8 245.3 4.1 81.4 5.4 253.8 4.1 256.8 4.1 434.1 11.1 120.2 5.9 284.0 5.0 169.4 4.9 74.7 10.5 261.0 3.5 226.4 3.4 595.2 9.0 176.7 2.5 153.6 2.3 208.1 2.7 301.8 4.6 481.4 7.4 521.1 7.3 604.7 9.0 146.0 2.5 236.6 3.6 508.0 8.8 436.1 6.4 270.1 4.6 314.9 5.0 552.4 8.6 232.1 4.2 257.1 4.3 541.2 8.1 369.8 6.7 165.9 3.7 245.3 4.2 152.3 3.6 79.4 5.9 199.1 3.8 154.5 4.9 205.2 4.2 244.8 10.7 176.5 4.5 156.5 4.2 25.7 12.4- 83.2 8.4 331.0 4.4 499.8 6.7 252.5 3.3 539.5 6.7 378.6 5.1 263.0 3.8 122.7 2.2 549.0 7.4 400.1 6.8 716.5 9.8 742.0 13.0 236.9 4.5 818.8 15.1 235.8 3.7 284.7 5.0 514.8 7.9 400.4 6.6 352.6 5.6 434.8 6.7 66.5 7.2 278.5 4.2 311.6 4.6 189.4 3.9 146.9 4.7 113.6 4.8 127.7 4.3 188.3 4.3 95.3 6.1 45.0 13.5 I380.6 6.0 95.0 6.1 t181.2 5.2 1 50.9 16.5 148.3 2.0 82.5 1.4 196.5 2.8 325.0 4.4 378.7 4.9 207.8 3.0 161.9 2.5 281.7 3.9 288.0 3.9 )298.9 4.7 1 268.7 4.2 2 739.5 10.9 13 603.1 9.1 14 260.1 8.0 15 534.4 7.6 16 112.4 4.8 17 537.7 7.5 18 159.4 4.0 19 261.0 6.1 20 335.1 5.6 21 146.3 4.4 22 163.9 3.5 23 155.0 4.1 24 172.8 3.7 25 60.2 8.5 26 190.8 4.3 27 226.1 4.1 28 88.0 8.0 29 28.2 11.6 30 86.6 8.1 31 73.4 11.0 32 153.9 6.0 33 117.1 6.9 1 473.7 9.4 2 390.5 5.2 3 375.2 4.8 4 249.8 3.4 5 461.0 6.4 6 247.8 3.3 7 440.7 6.2 8 708.0 9.5 9 116.2 2.3 10 482.4 7.6 11 184.6 3.0 12 1075.4 18.4 13 463.8 8.2 14 306.0 4.7 15 455.2 6.2 16 374.7 6.3 17 376.0 6.1 18 277.6 4.7 19 126.3 3.9 20 539.0 7.9 21 58.2 6.1 22 34.6 9.9 23 310.3 4.8 24 66.9 6.0 25 67.6 5.7 26 17.5 8.3 27 33.5 11.8 28 229.3 8.6 29 66.4 12.0 30 219.0 4.3 31 106.1 6.6 32 165.9 5.4 1 274.9 4.0 2 382.6 5.2 3 163.9 2.1 4 298.2 4.1 5 269.3 3.4 6 272.8 3.8 7 208.4 2.9 8 152.7 2.4 9 187.9 2.7 10 246.7 3.4 11 556.6 7.2 12 137.9 3.6 13 357.6 5.6 14 62.9 7.1 15 316.5 5.1 16 245.9 4.2 17 337.6 5.9 18 161.7 3.7 19 297.3 5.0 244.8 4.2 306.8 4.9 41.3 102.6 179.9 3.7 58.4 6.7 65.4 7.9 259.8 137.0 6.7 176.5 4.3 84.8 8.4 235.1 4.3 3331.3 328.1 4.3 207.2 2.7 329.9 319.0 4.6 632.0 8.9 213.2 3.2 316.6 3.8 125.2 2.4 271.2 4.2 400.2 5.9 435.7 6.3 451.0 6.3 561.1 7.6 670.3 9.6 61.9 7.1 169.6 3.6 220.2 3.6 248.7 4.2 197.1 3.9 352.6 5.1 400'7 5.9 48.2 10.4 162.7 74.4 6.6 66.2 8.4 213.1 3.9 223.1 5.4 161.7 5.2 126.8 7.2 119.3 130.8 4.8 79.3 7.7 67.9 1.6 264.6 3.3 167.6 2.2 284.9 3.8 230.1 472.3 7.9 426.6 603.7 8.9 756.7 13.0 769.6 11.0 201.7 4.4 338.0 4.6 250.0 607.4 10.7 361.9 132.6 4.1 338.7 5.1 1165.4 3.6 266.6 4.3 109.5 3.8 136.5 3.7 *69.9 9.7 169.0 6.1 t 24.1 9.8 588.3 5.4 i 74.1 6.1 7 296.0 9.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -99- 28 101.1 4.9 29 51.7 11.6 126.9 4.8 31 93.9 7.5 1 108.2 3.0 2 411.8 6.4 3 549.6 7.3 4 300.5 3. 9 296.0 3.8 6 141.5 2.3 7 421.4 6.0 8 595.5 9.6 9 161.9 2.6 104.7 4.6 11 480.6 8.2 12 361.3 5.7 13 570.0 8.1 14 380.2 5.9 455.5 6.8 16 316.6 4.8 17 379.0 6.9 18 240.6 4.9 19 294.5 4.5 218.6 3.7 21 253.1 4.3 22 204.0 3.7 23 22.5 10.3 24 168.3 3.5 112.6 4.3 26 251.3 4.2 27 166.2 4.2 29 89.0 5.8 71.8 11.6 31 139.1 4.8 1 216.6 6.3 2 588.4 8.4 3 331.0 4.3 4 449.6 5.6 253.7 3.4 6 300.2 4.0 7 642.4 10.8 8 403.5 5.4 9 420.1 6.9 709.7 12.4 11 412.9 7.3 12 383.4 5.8 13 668.5 10.3 14 235.9 3.9 395.4 5.6 16 234.7 3.9 17 249.6 4.3 18 227.7 3.8 19 184.8 3.2 42.8 10.8 21 38.3 10.3 22 115.0 3.7 23 377.8 6.6 24 40.4 9.4 123.9 4.1 26 210.4 15.3 27 247.9 6.6 28 111.0 5.9 29 164.8 4.3 244.9 4.5 31 17.8 8.8 2 181.6 3.5 3 542.5 7.2 4 390.8 5.5 1082.5 23.8 6 344.4 5.4 7 512.0 7.4 8 435.6 5.6 9 289.5 4.3 10 212.4 3.7 11 303.6 5.0 12 140.3 3.2 13 346.0 5.4 14 201.0 3.6 15 302.3 4.4 16 177.6 3.4 17 226.2 3.5 18 310.0 5.0 19 294.3 4.2 20 186.6 3.4 21 70.8 4.8 22 87.5 5.1 23 138.2 3.8 24 17. 3 8.6 25 186.5 3.8 26 153.0 6.3 27 103.2 5.9 28 233.9 4.2 29 237.4 5.1 30 98.1 5.1 1 757.0 20.2 2 461.7 8.1 3 536.4 6.7 4 676.8 8.9 5 93.3 2.8 6 205.7 3.5 7 223.6 3.2 8 71.8 4.5 9 169.1 3.3 10 255.8 3.8 11 359.6 6.3 12 546.1 10.0 13 289.9 5.1 14 222.8 3.6 15 553.8 8.6 16 121.7 4.1 17 544.4 7.8 18 111.8 5.8 19 173.6 3.3 20 302.9 4.3 21 144.0 4.0 22 220.1 4.0 23 53.8 6.4 24 265.7 4.3 25 1-35.9 9-3 26 227.2 4.3 27 138.1 4.2 28 329.2 5.2 29 202.0 4.2 30 188.4 5.0 1 625.3 16.3 2 516.7 8.9 3 318.8 4.8 4 68.4 2.6- 5 70.0 2.5 6 554.4 7.8 7 616.9 7.9 8 184.8 2.7 9 479.2 7.3 10 227.1 3.7 11 198.2 3.3 12 251.3 4.4 13 126.1 3.5 14 171.4 3.2 15 142.8 3.4 16 251.2 4.0 17 67.0 5.2 18 384.8 5.8 119 271.1 3.9 1 20 144.8 3.6 -2 21 2 -2 21 2 -2 21 2 -2 21 2 -2 21 2 -2 21 2 -2 21 2 -2 21 2 -2 21 2 -2 21 3 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 1 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 22 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 23 -2 24 -2 24 -2 24 -2 24 -2 24 218.4 3.8 190.3 3.6 281.5 4.6 65.5 8.6 87.3 7.6 89.6 5.3 114.9 4.3 212.4 4.7 121.0 4.9 194.7 4.9 330.9 8.9 171.2 3.1 230.8 4.0 190.1 4.0 199.2 2.8 45.2 4.2 252.9 3.8 326.5 5.5 442.0 7.9 351.1 5.0 221.3 3.7 90.9 3.5 63.2 5.0 62.2 4.8 256.6 3.9 212.1 3.4 136.2 3.3 56.1 6.2 212.9 3.5 89.7 3.8 40.5 8.6 113.9 3.9 217.3 3.8 261.9 11.8 182.4 4.0 145.8 4.3 217.0 4.9 169.9 4.5 61.5 11.1 111.8 4.1 371.8 7.7 337.2 5.0 421.9 5.3 90.1 2.2 416.2 6.3 175.8 3.0 81.5 3.7 1187.5 3.3 211.2 3.3 *240.6 3.8 362.2 4.9 *233.1 4.1 229.5 3.7 260.7 4.0 117.2 3.7 1306.3 4.7 79.6 4.5 I134.1 3.3 215.6 3.8 43.2 10.1 122.1 9.8 t 74.4 7.4 i71.4 5.6 i48.0 11.6 7 152.4 4.3 3128.5 4.7 157.0 5.4 610.3 11.8 198.9 2.8 95.6 1.9 184.9 2.6 256.8 3.7 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 24 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 25 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 -2 26 8 196.1 9 63.7 3 10 291.3 11 176.3 12 475.0 13 192.5 14 106.4 15 23.9 16 143.1 17 126.8 18 134.7 19 166.9 20 86.1 21 103.1 22 117.4 23 338.1 24 37.2 1 25 97.8 26 132.8 27 197.7 28 95.8 1 302.4 1 3 145.3 4 329.1 5 415.0 6 309.8 7 347.9 8 285.9 9 187.5 10 150.2 11 153.0 12 487.1 13 219.9 14 250.8 15 104.5 16 26.9 17 130.6 18 147.6 19 273.3 20 69.1 21 80.5 22 255.6 23 65.3 24 203.6 25 116.6 26 333.2 27 61.4 3 215.9 4 383.6 5 44.0 6 302.2 7 73.8 8 214.2 9 319.3 10 232.0 11 419.5 12 181.4 13 79.5 14 26.5 15 190.4 16 234.8 17 140.2 18 185.7 19 282.0 20 136.7 21 149.7 22 84.1 23 221.6 24 159.7 25 217.5 26 75.0 27 193.8 .6 7.1 3.4 3.2 9.9 .3 3.3 .3.2 4.6 3.9 15.4 .2.3 4.6 4.1 10.6 4.2 6.4 6. 1 4.3 4.6 4.1 2.9 2.9 2.8 3.4 4.1 10.0 3.2 3.9 4.7 7.1 8.1 7.8 4.1 4.2 6.6 4.6 2.3 2.9 4.3 3.2 5.7 2.8 3.3 9.2 3.1 3.3 3.3 3.6 4.1 4.3 5.3 4.6 3.7 4.6 7.1 4.4 SUBSTITUTE SHEET (RULE 28) WO 99/10379 PCT/GB98/02542 -100- -2 27 3 418.5 10.0 -2 30 7 69.1 2.5 -2 34 7 125.4 2.9 -2 40 12 115.0 3.7 -2 27 4 310.1 5.4 -2 30 8 216.7 3.3 -2 34 8 189.1 3.2 -2 41 7 13.0 5.4 -2 27 5 384.8 7.0 -2 30 9 36.8 5.3 -2 34 9 20 .1 6.5 -2 41 9 184.5 3.6 -2 27 6 374.8 6.5 -2 30 10 81.3 2.5 -2 34 10 114.2 2.6 -I 0 2 29.7 -2 27 7 119.2 2.4 -2 30 11 98.2 2.5 -2 34 11 57 .0 5.0 -1 0 4 209.7 5.7 -2 27 8 91.5 2.4 -2 30 12 47.3 4.7 -2 34 12 219.8 5.8 -1 0 5 289.3 7.2 -2 27 9 194.8 3.1 -2 30 13 150.1 2.9 -2 34 13 11.0 5.5 -I1 0 6 309.3 7.9 -2 27 10 444.4 6.1 -2 30 14 219.4 3.6 -2 34 14 39 .8 6.5 -1 0 7 438.9 10.9 -2 27 11 453.7 6.4 -2 30 15 129.6 3.1 -2 34 15 146.6 3.2 -1 0 8 111.1 5.1 -2 27 12 348.0 5.7 -2 30 16 144.8 2.9 -2 34 16 94.4 4.0 -1 0 9 222.0 5.3 -2 27 13 261.9 3.7 -2 30 17 225.0 3.9 -2 34 17 84.2 4.1 -1 0 10 462.2 10.0 -2 27 14 223.9 3.4 -2 30 18 82.3 8.1 -2 34 18 24 .2 10.1 -1 0 11 337.2 -2 27 15 119.4 2.9 -2 30 19 215.1 3.8 -2 34 19 213.2 4.2 -I1 0 12 107.3 4.8 -2 27 16 167.6 3.5 -2 30 20 249.2 3.9 -2 34 20 154.7 3.2 -I1 0 13 400.9 -2 27 17 87.5 5.0 -2 30 21 130.3 3.6 -2 35 5 31 .9 3.2 -1 0 14 96.7 5.8 -2 27 18 217.6 3.3 -2 30 22 203.5 3.7 -2 35 7-223.7 4.0 -1 0 15 12.0 8.7 -2 27 19 93.3 4.5 -2 30 23 55.3 8.3 -2 35 8 169.5 2.5 -1 0 16 277.3 6.1 -2 27 20 104.1 4.5 -2 30 24 156.8 3.7 -2 35 9 24.5 7.6 -1 '0 17 152.9 9.3 -2 27 21 96.6 4.7 -2 31 5 225.2 6.8 -2 35 10 193.4 4.4 -1 0 18 551.0 11.7 -2 27 22 163.7 5.0 -2 31 6 229.9 3.8 -2 35 11 41.0 6.5 -1 0 19 261.2 6.9 -2 27 23 143.8 4.8 -2 31 7 127.1 2.1 -2 35 12 206.0 3.7 -1 0 20 590.2 13.9 -2 27 24 163.8 4.7 -2 31 8 60.3 2.4 -2 35 13 109.8 2.8 -I1 0 21 84.2 -2 2725 22.2 10.9 -2 31 9 229.8 3.1 -2 35 14 41.1 6.8 1 0 22 132.1 5.9 -2 27 26 59.1 7.2 -2 31 10 291.5 3.8 -2 35 15 169.4 3.1 -I1 0 23 209.0 5.7 -2 28 4 135.7 4.0 -2 31 11 176.1 2.9 -2 35 16 86.2 3.8 -1 0 24 72.3 7.1 -2 28 5 175.3 3.7 -2 31 12 228.0 3.3 -2 35 17 145.5 3.0 -1 0 25 59.7 14.3 -2 28 6 652.1 10.2 -2 31 13 107.1 2.8 -2 35 18 40.2 8.4 -1 0 26 232.1 -2 28 7 445.6 6.2 -2 31 14 200.7 3.5 -2 35 19 80.0 5.2 -1 0 27 164.3 6.3 -2 28 8 156.8 2.5 -2 31 15 133.4 2.9 -2 36 6 51.4 6.5 -1 0 28 78.1 9.1 -2 28 9 217.7 3.3 -2 31 16 67.2 5.4 -2 36 7 266.1 8.7 -1 0 29 67.4 13.5 -2 28 10 226.8 3.2 -2 31 17 58.8 5.4 -2 36 8 147.8 5.5 -1 0 30 390.5 15.4 -2 28 11 277.8 3.9 -2 31 18 273.8 4.5 -2 36 9 140.9 2.3 -1 0 31 167.7 7.4 -2 28 12 466.1 6.7 -2 31 19 38.9 8.0 -2 36 10 363.3 5.8 -1 0 32 83.6 10.5 -2 28 13 178.2 2.7 -2 31 20 138.4 3.5 -2 36 11 233.9 4.1 -1 0 33 24.3 17.3 -2 28 14 93.3 2.9 -2 31 21 79.0 6.7 -2 36 12 215.9 3.5 -1 0 34 23.6 16.0 -2 28 15 155.1 2.8 -2 31 22 171.3 4.5 -2 36 13 219.9 3.7 -1 1 2 25.4 2.1 -2 28 16 10.8 5.4 -2 31 23 72.3 6.8 -2 36 14 154.1 3.5 -I1 1 4 378.5 -2 28 17 198.0 3.4 -2 32 6 113.8 2.9 -2 36 15 279.1 4.1 -1 1 5 229.2 6.2 -2 28 18 243.3 4.3 -2 32 7 73.2 3.0 -2 36 16 409.2 5.7 -1 1 6 195.8 3.4 -2 28 19 68.9 7.9 -2 32 8 93.3 1.9 -2 36 17 295.7 4.7 -1 1 7 117.7 2.3 -2 28 20 122.5 6.2 -2 32 9 38.3 3.9 -2 36 18 104.1 4.5 -1 1 8 264.0 4.3 -2 28 21 92.2 5.6 -2 32 10 285.1 4.2 -2 37 7 46.2 4.2 -1 1 9 452.0 6.8 -2 28 22 102.3 4.1 -2 32 11 210.5 3.0 -2 37 8 180.5 3.7 -1 1 10 180.4 2.8 -2 28 23 131.5 4.5 -2 32 12 301.9 4.0 -2 37 9 271.1 4.5 I I 11 304.3 4.2 -2 28 24 93.5 5.3 -2 32 13 144.9 2.8 -2 37 10 166.7 2.8 -1 1 12 386.0 5.4 -2 28 25 73.4 5.7 -2 32 14 133.9 3.0 -2 37 11 122.0 2.5 -1 1 13 361.4 4.9 -2 28 26 86.3 7.0 -2 32 15 231.6 6.0 -2 37 12 182.0 2.9 -1 1 14 275.9 -2 29 4 384.5 10.2 -2 32 16 198.7 3.5 -2 37 13 111.9 2.7 -1 1 15 368.9 5.8 -2 29 5 320.0 6.4 -2 32 17 236.1 4.2 -2 37 14 158.8 3.4 -1 1 16 547.0 7.3 -2 29 6 120.3 2.5 -2 32 18 144.6 3.3 -2 37 15 33.1 8.0 -1 1 17 252.0 5.4 -2 29 7 147.3 2.3 -2 32 19 142.2 3.2 -2 37 16 157.9 3.0 -1 1 18 487.2 7.4 -2 29 8 253.1 3.9 -2 32 20 213.2 3.9 -2 37 17 193.6 3.9 -1 1 19 277.1 4.8 -2 29 9 154.2 2.5 -2 32 21 166.6 4.1 -2 38 6 312.7 8.5 -I1 1 20 458.0 -2 29 10 184.2 2.8 -2 32 22 81.4 4.6 -2 38 8 177.5 4.3 -1 1 21 273.0 4.7 -2 29 11 81.1 2.8 -2 33 5 123.6 2.4 -2 38 9 62.3 4.0 -1 1 22 189.4 3.8 -2 29 12 157.9 3.2 -2 33 6 156.8 3.1 -2 38 10 111.2 2.2 -1 1 23 64.3 10.7 -2 29 13 308.6 4.3 -2 33 7 127.3 2.0 -2 38 11 94.6 2.3 -1 1 24 152.3 3.7 -2 29 14 221.6 3.4 -2 33 8 29.8 4.6 -2 38 12 200.4 3.6 -1 1 25 244.4 3.9 -2 29 15 140.6 2.8 -2 33 9 61.5 2.7 -2 38 13 95.3 2.7 -1 1 26 168.3 3.7 -2 29 16 130.4 2.9 -2 33 10 125.6 2.4 -2 38 14 30.9 9.1 -1 1 27 106.5 5.8 -2 29 17 526.3 8.2 -2 33 11 115.5 2.4 -2 38 15 106.0 3.7 -1 1 28 163.8 3.8 -2 29 18 253.6 4.4 -2 33 12 237.9 3.5 -2 39 8 89.0 2.9 -1 1 29 196.9 4.1 -2 29 19 207.0 5.0 -2 33 13 109.0 3.2 -2 39 9 182.7 4.4 -1 1 30 354.0 10.1 -2 29 20 226.9 3.7 -2 33 14 183.8 7.1 -2 39 10 43.7 4.0 -1 1 31 93.0 7.8 -2 29 21 317.4 5.1 -2 33 15 73.6 6.8 -2 39 11 93.1 2.4 -1 1 32 98.3 6.1 -2 29 22 311.8 5.0 -2 33 16 29.0 9.0 -2 39 12 66.7 3.2 -1 1 33 114.8 8.7 -2 29 23 198.6 4.1 -2 33 17 63.3 4.8 -2 39 13 165.8 3.0 -1 1 34 124.1 -2 29 24 166.3 4.1 -2 33 18 131.5 3.9 -2 39 14 18.9 8.5 -1 2 1 4.3 2.1 -2 29 25 89.5 5.5 -2 33 19 56.5 5.7 -2 40 8 101.3 4.0 -1 2 3 204.9 12.0 -2 30 4 61.9 3.8 -2 33 20 63.1 6.0 -2 40 9 105.6 3.2 -1 2 4 87.1 -2 30 5 105.5 2.4 -2 33 21 136.8 4.0 -2 40 10 109.8 2.8 -1 2 6 162.0 3.1 -2 30 6 223.3 3.7 -2 34 6 46.1 4.5 -2 40 11 12.8 5.9 -1 2 7 497.0 9.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -101- 2 8 166.3 2.8 2 9 66.8 3.8 2 10 255.9 3.8 2 11 121.1 2.7 2 12 195.0 3.2 2 13 699.9 10.3 2 14 746.1 10.2 2 15 194.7 3.6 2 16 688.4 9.8 2 17 483.9 6.7 2 18 381.6 5.6 2 19 400.3 6.6 2 20 262.3 4.7 2 21 74.6 6.3 2 22 172.8 3.6 2 23 104.5 6.9 2 24 73.0 5.7 2 25 102.1 4.4 2 26 184.0 3.6 2 27 295.3 4.1 2 28 194.0 3.7 2 29 124.1 5.2 2 30 337.8 10.7 2 31 159.6 5.4 2 32 113.2 6.3 2 33 117.1 10.7 2 34 18.1 9.1 3 4 284.7 5.7 3 5 571.6 9.6 3 6 278.8 5.5 3 7 277.7 4.7 3 8 104.1 2.5 3 9 302.9 4.6 3 10 162.4 2.7 3 11 239.9 3.8 3 12 593.1 8.6 3 13 919.0 12.8 3 14 412.6 5.8 3 15 126.3 4.0 3 16 531.0 7.1 3 17 507.8 7.1 3 18 544.4 9.1 3 19 163.2 4.4 3 20 39.4 15.2 3 21 230.9 4.2 3 22 106.1 4.8 3 23 38.7 12.2 3 24 209.5 4.2 3 25 260.8 4.1 3 26 34.9 12.0 3 27 134.5 4.2 -3 28 145.5 4.0 3 29 132.3 4.7 3 30 374.9 11.8 3 31 157.0 4.8 3 32 187.2 5.0 3 33 86.9 9.7 3 34 171.6 6.5 4 2 185.7 7.6 4 3 316.1 7.8 4 4 799.9 23.8 4 5 460.0 8.9 4 6 247.6 4.0 4 7 535.9 7.8 4 8 263.9 5.3 4 9 340.4 5.2 4 10 182.6 2.7 4 11 310.6 4.7 4 12 326.7 4.6 4 13 598.8 8.4 4 14 538.6 7.3 4 15 541.8 7.9 4 16 494.9 6.4 4 17 283.2 5.5 4 18 786.5 11.9 4 19 172.4 3.8 4 20 236.9 4.3 4 21 83.7 5.9 4 22 114.7 4.0 4 23 17.9 8.7 4 24 421.7 6.4 4 25 133.4 4.6 4 26 380.2 5.4 4 27 263.1 4.1 4 28 55.8 8.6 4 29 164.1 5.0 4 30 220.1 13.0 4 31 98.9 6.7 4 32 170.1 5.7 4 33 126.5 7.1 4 34 39.4 14.4 5 1 293.2 6.4 5 2 543.8 23.4 5 3 549.0 9.3 5 4 251.7 5.3 5 5 17.9 5.2 5 6 378.0 6.1 5 7 327.6 5.1 5 8 553.6 10.0 5 9 265.7 4.5 5 10 312.7 4.5 5 11 171.9 3.0 5 12 65.5 4.0 5 13 511.7 6.4 5 14 797.0 10.6 5 15 172.6 3.2 5 16 436.9 5.8 5 17 164.8 6.0 5 18 986.6 15.5 5 19 102.6 6.0 5 20 257.2 4.4 5 21 278.4 4.8 5 22 206.3 3.8 5 23 97.9 5.1 5 24 222.0 4.1 5 25 177.8 3.5 5 26 201.8 3.7 5 27 130.8 6.8 5 28 139.8 4.1 5 29 123.9 4.8 5 30 68.4 11.3 5 31 205.0 4.8 5 32 125.4 6.0 5 33 145.7 6.2 5 34 26.4 12.0 6 1 418.9 7.6 6 2 114.9 2.3 6 3 647.0 16.4 6 4 497.4 10.4 6 5 628.1 12.1 6 6 630.3 8.7 6 7 364.4 6.7 6 8 175.3 2.9 6 9 455.3 6.6 6 10 417.3 7.4 6 11 274.0 3.8 6 12 319.8 4.7 6 13 431.2 6.1 6 14 1039.7 14.8 6 15 754.0 10.3 6 16 386.8 5.5 6 17 379.3 5.5 6 18 410.2 6.1 6 19 312.7 5.4 6 20 442.7 6.7 6 21 303.6 5.0 6 22 334.0 5.0 6 23 282.8 4.7 6 24 342.5 5.7 6 25 136.7 3.9 6 26 62 .8 6.5 6 27 208.6 3.9 6 28 38.5 11.4 6 29 62.0 9.7 6 30 162.3 5.1 6 31 127.2 5.3 6 32 88.7 7.4 6 33 283.9 5.2 6 34 26.2 12.4 7 1 222.2 4.3 7 2 510.8 12.0 7 3 314.0 5.2 7 4 194.7 3.2 7 5 254.0 3.8 7 6 709.4 11.5 7 7 80.7 2.6 7 8 57.0 3.4 7 9 237.8 3.8 7 10 473.5 6.4 7 11 427.5 5.5 7 12 655.1 9.0 7 13 556.4 8.4 7 14 530.8 7.4 7 15 139.7 3.3 7 16 346.0 5.6 7 17 313.4 4.9 7 18 70.7 15.4 7 19 83.4 6.2 7 20 232.9 4.2 7 21 178.2 4.1 7 22 77.5 5.8 7 24 242.2 4.1 7 25 184.1 3.7 7 26 176.0 4.1 7 27 71.9 7.8 7 28 199.1 3.9 7 30 119.4 7.3 7 31 101.9 8.6 7 3 2 89.0 8.9 7 33 59.1 12.3 7 34 80.8 10.7 8 1 104.6 1.9 8 2 130 .2 2.2 8 3 432.5 5.9 8 4 242.3 3.7 8 5 407.6 6.1 8 6 227.9 3.7 8 7 122.2 2.5 8 8 291.8 4.1 8 9 514.1 7.5 8 10 405.4 6.1 8 11 182.6 3.0 8 12 485.2 7.1 8 13 187.4 3.2 8 14 394.5 5.6 8 15 324.5 4.9 8 16 297.1 7.8 8 17 232.9 5.4 8 18 356.1 5.5 8 19 151.8 4.1 8 20 384.5 6.2 8 21 398.5 5.3 8 22 284.5 4.4 8 23 513.6 7.9 8 24 324.5 5.0 8 25 79.2 5.4 PCT/GB98/02542 1 8 26 332.3 4.9 1 8 27 102.6 1 8 28 337.4 1 8 29 61.1 23.9 1 8 30 129.0 5.9 1 8 31 103.8 7.4 1 8 32 207.1 5.4 1 8 33 140.6 19 2 357.8 5.9 1 9 3 473.2 6.6 1 9 4 16.5 5.7 1 9 5 455.0 6.9 19 6 308.4 5.1 19 7 71.8 2.4 1 9 8 704.3 12.0 1 9 9 237.0 3.3 1 9 10 433.9 1 9 11 368.6 5.4 1 9 12 1016.9 13.7 1 9 13 607.9 8.8 1 9 14 185.7 3.3 1 9 15 221.1 4.3 1 9 16 278.5 4.2 1 9 17 464.1 1 9 18 232.7 4.7 1 9 19 209.5 3.8 1 9 20 585.9 8.6 1 9 21 213.7 4.4 1 9 22 193.9 1 9 23 266.4 1 9 24 403.8 1 9 25 178.3 1 9 26 148.7 4.3 1 9 27 246.1 4.3 1 9 28 95.6 5.4 1 9 29 369.7 8.6 1 9 30 222.7 5.4 1 9 31 240.0 5.8 1 9 32 159.5 5.4 1 9 33 71.4 1 10 1 425.7 8.4 1 10 2 391.3 5.9 1 10 3 243.0 3.7 1 10 4 172.1 2.8 1 10 5 143.8 2.2 1 10 6 350.1 5.3 1 10 7 340.6 4.8 1 10 8 399.9 5.4 1 10 9 261.1 3.9 1 10 10 691.7 10.2 1 10 11 309.4 1 10 12 302.7 4.3 1 10 13 405.6 5.3 1 10 14 685.8 10.2 1 10 15 273.8 4.6 1 10 16 619.7 8.2 .1 10 17 854.0 14.6 1 10 18 387.1 5.8 .1 10 19 91.9 4.9 1j 10 20 489.1 7.4 1 10 21 125.4 4.8 *1 10 22 307.3 -1 10 23 115.3 3.6 .1 10 24 233.7 3.9 1 10 25 61.3 1 10 26 225.6 3.8 -1 10 27 149.6 3.6 -1 10 28 145.5 4.4 1I 10 29 243.3 13.1 -l1 10 30 274.3 5.3 1 10 31 77.2 1 10 32 151.6 5.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -102- 1 10 33 45.3 14.9 1 13 6 52.0 2.6 -1 15 15 345.5 5.5 -1 17 25 58.0 8.1 I I 1 1 205.1 3.9 1 13 7 464.2 6.5 1 15 16 256.0 4.8 -1 17 26 169.4 3. 7 I 11 2 269.1 3.7 -I1 13 8 195.4 2.9 1 15 17 317.4 5.4 1 17 27 144.0 6.2 I 11 3 349.0 4.6 1 13 9 609.8 7.8 1 15 18 251.9 5.7 1 17 28 140.1 I 11 4 695.9 10.6 1 13 10 249.8 3.5 -I1 15 19 271.4 5.2 1 17 29 138.8 4.2 -I 11 5 133.6 2.3 1 13 11 638.7 8.2 1 15 20 317.6 5.2 -I1 17 30 102.5 6.2 11I 6 66.4 2.6 1 13 12 475.6 6.2 -I 1IS 21 497.9 8.0 -I1 17 31 40.6 13.6 -I 11 7 501.6 8.3 1 13 13 525.8 8.0 -I 1I1 22 131.4 4.5 1 18 2 192.0 3.4 -I 11 8 323.0 4.6 1 13 14 487.7 7.3 1 15 23 144.7 3.1 -1 18 3 195.9 2.9 -I 11 9 284.5 4.0 1 13 15 281.0 5.5 -1 15 24 83.7 5.1 -I1 18 4 580.6 7.3 -1 11 10 480.3 7.1 1 13 16 726.4 10.8 1 15 25 134.9 3.6 1 18 5 181.3 -1 11 11 876.9 14.2 1 13 17 282.6 4.6 1 15 26 195.8 3.6 -I1 18 6 1125.9 22.9 I 11 12 441.3 5.9 1 13 18 400.6 6.2 1 15 27 15.3 7.7 -I1 18 7 276.3 4.1 -lI 11 13 22.3 9.2 1 13 19 243.9 4.2 1 15 28 241.1 4.4 1 18 8 451.8 6.7 I 11 14 378.1 5.4 1 13 20 209.9 3.8 1 15 29 178.5 4.3 1 18 9 353.8 5.4 -1 I 1 15 595.4 8.0 -I1 13 21 236.4 4.0 1 15 30 102.6 5.6 1 18 10 45.2 I 11 16 450.8 6.6 1 13 22 180.5 3.4 1 15 31 232.9 4.5 1 18 11 489.7 -1I 11 17 198.4 3.7 1 13 23 257.7 3.9 1 15 32 65.1 9.3 1 18 12 16.7 -1I 11 18 426.7 7.1 1 13 24 180.4 3.5 1 16 1 246.1 5.9 1 18 13 271.8 -1 I 1 19 153.5 3.6 1 13 25 264.5 4.2 1 16 3 96.6 2.0 1 18 14 357.0 5.9 -1I 11 20 157.5 3.7 1 13 26 89.8 5.4 1 16 4 333.9 5.0 1 18 15 219.0 3.4 -1I 11 21 274.8 4.3 1 13 27 170.5 4.5 1 16 5 171.9 2.9 -l 18I 16 216.8 3.9 -1I 11 22 166.6 4.1 -I1 13 28 281.6 12.5 1 16 6 614.1 8.5 1 18 17 65.5 5.2 -1I 11 23 79.3 5.6 1 13 29 184.2 4.3 1 16 7 680.7 9.5 -I1 18 18 76.4 5.3 -11 24 174.3 4.1 1 13 30 285.3 6.2 1 16 8 414.3 5.9 1 18 19 119.4 3.3 I1 11 25 180.2 4.3 -I1 13 31 121.7 6.2 1 16 9 452.5 5.9 1 18 20 98.7 3.6 I1 11 26 263.3 4.1 1 13 32 82.1 8.1 1 16 10 738.9 11.6 1 18 21 80.4 4.4 I1 11 27 89.9 5.7 1 14 1 10.5 4.7 1 16 11 369.9 5.1 1 18 22 34.7 9.1 I1 11 28 106.7 5.6 1 14 2 368.0 6.9 1 16 12 34.2 9.8 1 18 23 158.9 3.4 I1 11 29 23.3 11.5 1 14 3 227.0 3.1 1 16 13 321.8 5.7 -l1 18.24 90.3 5.3 -1 11 30 191.7 5.2 1 14 4 152.1 2.0 1 16 14 571.5 9.0 1 18 25 179.5 3.6 -1 11 31 65.5 9.5 1 14 5 197.6 2.5 1 16 15 164.7 3.9 1 18 26 38.6 15.7 -1 11 32 78.4 12.3 1 14 6 506.1 8.3 1 16 16 236.5 3.9 1 18 27 70.7 7.3 I11I 33 54.8 11.5 1 14 7 39.1 4.0 1 16 17 192.6 3.6 -l1 18 28 121.3 5.1 -1 12 1 282.2 5.9 1 14 8 830.1 12.1 1 16 18 299.0 4.7 1 18 29 182.6 -1 12 2 334.1 4.8 1 14 9 202.8 3.7 1 16 19 84.4 3.8 1 18 30 67.3 7.9 -1 12 3 100.9 1.5 1 14 10 789.4 12.0 1 16 20 452.6 7.2 1 18 31 98.3 7.4 -1 12 4 536.7 8.3 1 14 11 599.3 9.0 1 16 21 210.8 3.8 1 19 3 509.5 10:1 -1 12 5 97.3 2.1 1 14 12 193.7 3.5 1 16 22 339.4 5.2 1 19 4 746.7 9.4 -1 12 6 372.5 5.2 1 14 13 322.4 5.2 1 16 23 97.5 4.3 1 19 5 46.4 3.2 -1 12 7 423.5 6.5 1 14 14 344.6 5.0 1 16 24 90.2 4.4 -l1 19 6 531.8 7.2 -1 12 8 493.0 7.2 1 14 15 296.2 4.8 1 16 25 130.8 3.5 1 19 7 285.6 3.7 -1 12 9 123.3 2.6 1 14 16 175.6 3.6 1 16 26 148.8 4.2 1 19 8 492.4 8.6 -1 12 10 400.8 5.5 -I1 14 17 160.0 3.5 1 16 27 223.6 12.4 1 19 9 850.0 12.2 1 12 11 555.4 8.0 1 14 18 140.0 4.8 1 16 28 124.6 4.9 1 19 10 220.4 3.7 1 12 12 287.2 4.5 1 14 19 126.8 5.3 1 16 29 85.6 6.4 -I1 19 11 219.3 3.2 1 12 13 278.8 4.2 1 14 20 165.4 4.1 1 16 30 152.0 4.2 1 19 12 203.7 3.2 1 12 14 335.0 5.2 1 14 21 279.6 4.2 1 16 31 77.3 7.9 1 19 13 153.3 3.3 1 12 15 383.4 6.1 1 14 22 53.3 6.4 1 17 1 442.4 10.0 1 19 14 120.7 3.7 1 12 16 448.6 6.7 1 14 23 242.5 3.6 1 17 2 69.5 2.3 1 19 15 189.8 1 12- 17 337.0 5.2 -I1 14 24 253.7 4.1 1 17 3 793.6 10.5 -l1 19 16 157.9 4.4 -l1 12 18 467.3 6.5 1 14 25 276.0 4.3 1 17 4 71.8 1.8 1 19 17 256.7 1 12 19 300.1 4.7 1 14 26 302.1 4.5 1 17 5 452.7 6.6 1 19 18 158.6 3.2 1 12 20 27.4 10.5 -I1 14 27 177.2 4.3 1 17 6 132.5 2.3 1 19 19 307.2 4.4 1 12 21 135.0 3.5 1 14 29 37.8 12.4 1 17 7 293.7 4.3 1 19 20 154.4 1 12 22 67.5 7.2 1 14 30 120.7 5.4 1 17 8 356.9 4.8 1 19 21 217.3 3.4 1 12 23 211.2 3.5 -I1 14 31 92.5 7.5 1 17 9 647.3 9.6 1 19 22 46.6 9.8 1 12 24 149.8 4.1 1 14 32 223.9 4.6 1 17 10 305.6 4.8 1 19 23 .156.7 3.4 1 12 25 323.8 5.2 1 15 1 382.3 11.3 1 17 11 667.5 9.0 -l1 19 24 169.5 1 12 26 219.4 4.5 1 15 2 376.8 7.3 1 17 12 705.4 9.1 1 19 25 21.3 9.9 -l1 12 27 89.4 6.0 1 15 3 63.3 1.7 -I1 17 13 132.8 3.3 1 19 26 207.0 1 12 28 230.1 5.1 1 15 4 424.9 5.8 1 17 14 160.9 4.1 1 19 27 56.4 7.1 1 12 29 123.7 4.7 1 15 5 701.0 9.6 1 17 15 134.4 3.4 1 19 28 156.1 1 12 30 70.3 10.1 1 15 6 193.3 2.6 1 17 16 701.1 11.3 1 19 29 155.6 4.9 1 12 31 139.8 5.6 1 15 7 408.7 5.6 1 17 17 289.1 4.1 1 19 30 153.2 4.9 1 12 32 205.6 4.9 1 15 8 324.4 5.4 1 17 18 317.5 4.8 -l1 20 2 248.7 6.9 1 12 33 95.8 8.3 1 15 9 16.7 7.4 -I1 17 19 458.0 5.9 -l1 20 3 180.5 5.1 -l1 13 1 229.2 6.3 1 15 10 581.9 8.0 1 17 20 120.0 3.5 -l1 20 4 678.5 10.4 1 13 2 194.5 2.7 1 15 11 374.2 5.3 1 17 21 282.2 4.1 1 20 5 513.4 6.3 1 13 3 63.8 1.9 -l1 15 12 423.4 6.4 1 17 22 292.4 4.4 1 20 6 703.1 9.3 -l1 13 4 161.5 2.5 1 15 13 780.7 10.8 1 17 23 103.4 4.0 1 20 7 333.2 4.9 1 13 5 255.3 3.9 1 15 14 108.6 6.4 1 17 24 146.8 3.5 1 20 8 219.9 4.8 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -103- 148.1 3.8 112.1 3.1 405.6 5.5 783.3 10.7 480.2 7.4 383.3 5.5 142.0 3.1 340.8 4.8 20.2 9.5 67.3 4.7 443.1 6.5 483.0 7.1 102.5 3.6 165.7 3.2 145.3 3.7 220.0 3.8 78.0 7.2 219.1 3.9 62.0 7.8 205.2 4.2 64.6 9.0 163.5 4.9 233.2 4.8 425.3 7.2 321.7 4.6 196.1 3.2 145.1 2.9 365.0 4.9 555.7 8.4 419.4 6.0 121.5 3.4 253.7 4.3 171.4 3.1 162.3 3.2 77.9 4.0 154.7 3.4 332.4 4.8 287.8 3.9 256.9 4.0 134.3 4.0 248.4 4.2 229.2 3.5 156.7 3.6 114.1 5.8 121.5 11.5 119.2 4.5 108.3 5.4 62.3 7.9 145.0 4.4 90.0 9.2 353.2 10.6 474.0 13.7 148.0 3.2 72.6 2.8 545.6 7.1 412.0 5.1 692.7 10.0 769.4 11.2 569.5 7.7 I106.1 2.8 150.3 2.9 342.8 5.8 241.0 3.8 431.3 5.8 186.4 3.1 184.9 3.2 222.5 3.7 148.2 5.5 141.9 3.2 135.2 3.6 1124.3 4.1 240.7 4.0 283.6 4.4 202.6 16.7 112.3 3.9 251.5 5.3 72.7 6.9 69.5 8.0 26.5 12.1 63.9 2.5 285.6 7.4 73.3 3.0 481.2 6.9 190.4 2.7 555.0 8.2 135.6 2.4 439.1 6.1 503.3 6.7 400.2 5.7 389.3 6.0 513.8 8.6 255.7 3.9 99.8 3.7 298.2 4.2 218.9 3.3 158.0 3.0 213.8 3.4 180.5 3.2 40.9 10.8 122.8 3.7 239.8 4.2 108.4 4.6 162.4 4.6 197.5 4.0 208.5 4.3 113.5 6.1 95.2 6.9 265.0 7.2 332.6 5.6 612.5 8.5 499.2 7.5 277.3 3.9 380.1 5.6 I406.1 6.5 261.8 3.8 448.6 6.4 239.9 3.8 284.9 5.0 263.7 3.5 200.0 3.2 267.4 3.8 162.8 5.6 213.3 3.4 133.7 3.2 1295.9 4.4 !92.3 4.7 1 248.7 10.6 1213.7 4.4 5121.3 3.7 i124.9 4.3 7 19.5 9.9 3 67.6 6.6 295.9 6.0 772.5 11.5 335.5 5.0 32.4 4.5 79.6 2.4 383.3 6.0 D 110.3 2.6 1 412.1 5.9 2 119.1 3.2 3 309.6 5.2 4 144.0 2.7 5 102.8 3.0 107.1 4.1 144.5 3.0 194.2 3.4 219.3 3.6 98.7 5.4 141.9 3.2 216.4 12.2 156.9 4.8 106.2 4.9 157.1 4.8 104.3 5.9 217.2 4.1 90.3 10.2 336.8 9.3 171.7 3.4 153.8 2.2 169.3 2.7 373.6 5.3 97.3 2.8 328.2 4.9 178.5 2.7 445.9 5.8 192.0 3.0 277.8 4.1 254.0 3.8 165.8 2.8 383.5 5.2 200.0 3.3 164.6 3.2 150.3 3.2 225.2 4.1 131.3 4.5 258.4 4.3 116.6 4.5 191.9 4.0 145.0 4.2 221.5 4.1 186.1 5.1 340.1 8.1 405.2 7.6 487.8 6.3 231.0 4.2 187.4 2.7 1 200.5 3.5 215.6 3.0 534.1 7.2 373.7 5.7 304-5 4.4 i251.9 3.8 i120.8 2.9 F 171.6 3.6 184.1 4.9 )99.9 4.6 )38.5 11.9 1 145.2 4.9 Z 251.6 3.8 3 179.0 4.4 t 48.4 9.4 5 205.1 3.9 5 192.4 4.0 37.3 2.6 269.2 6.5 247.6 4.3 200.6 3.1 150.9 2.4 175.1 2.6 109.3 2.4 0 108.1 2.7 1 96.8 2.7 2 441.2 6.1 3 402.9 5.6 4 191.9 3.0 176.0 2.8 37.2 9.6 292.8 282.7 4.6 199.1 212.4 139.0 3.7 100.7 4.2 113.3 4.4 161.1 4.9 190.3 4.8 29.4 13.4 222.2 6.1 173.0 356.1 76.2 2.2 58.8 239.0 3.8 109.5 313.2 4.1 238.2 3.8 372.6 4.9 161.2 2.9 271.5 3.8 279.6 3.9 392.0 5.7 142.3 11.6 128.0 3.3 227.1 4.1 119.5 304.4 4.8 115.6 4.1 216.3 167.8 2.6 244.3 3.7 55.2 3.1 293.2 4.3 I136.0 2.3 213.0 3.1 96.2 2.6 128.3 2.6 50.9 i134.6 3.4 12.5 6.1 78.5 4.6 169.2 11.5 207.9 124.4 1 102.7 4.4 114.3 4.3 3 159.6 3.7 t 71.8 7.3 187.5 6.8 144.6 162.4 2.9 128.5 2.3 81.0 2.2 ~3 173.4 2.7 1 293.5 3.8 2 172.1 2.8 3 202.3 2.9 4 283.3 5 67.6 4.2 6 196.7 4.2 7 186.1 4.9 8 202.1 3.8 9 67.8 0 400.0 6.1 1 131.8 4.3 2 200.3 3 109.1 5 159.2 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -104- 32 32 32 32 32 32 32 32 32 32 .32 32 32 32 32 32 33 33 33 33 33 33 33 33 .33 33 33 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 135 1 35 1 35 1 35 1 35 1 35 1 36 1 36 1 36 1 3R 1 3R 1 3R 1 3( 1 3( 1 3( 7 137.3 8 97.51 9 46.6 3 10 252.1 11 174.6 12 332.2 13 162.2 14 17.4 15 137.3 16 200.6 17 196.3 18 214.2 19 221.5 20 142.6 21 141.0 22 67.1 6 184.8 7 214.2 8 35.0 3 9 71.8 10 155.5 11 49.0 12 55.6 13 131.5 14 244.5 15 184.5 16 339.4 17 194.4 18 182.1 19 174.9 20 145.3 21 116.5 22 116.4 6 134.5 7 124.7 8 131.8 9 134.2 10 203.5 11 11.1 12 110.7 13 107.1 14 72.2 15 148.6 16 184.5 17 186.6 18 198.8 19 84.2 20 237.0 21 98.1 5 81.3 7 174.4 8 79.2 9 60.2 10 250.1 11 123.7 12 303.7 13 285.2 14 186.7 15 140.5 16 137.2 17 158.1 18 13.9 19 21.3 7 210.6 8 181.4 9 12.5 10 143.1 11 181.2 12 82.8 5 13 133.5 5 14 98.8 5 15 147.2 .9 .4 3.5 2.7 4.7 2.8 7.9 10.6 3.9 4.1 3.9 4.0 3.8 4.0 6.3 3.8 4.4 1.6 1.7 2.5 3.9 3.9 3.0 5.2 3.3 6.0 3.8 3.3 4.4 3.7 3.9 5.1 4.3 3.1 2.4 2.5 3.2 5.4 7.3 3.8 4.6 3.1 3.5 4.5 3.5 4.4 4.1 5.6 2.6 3.8 2.6 3.1 6.5 3.1 4.4 4.0 3.2 3.4 3.0 3.3 6.8 9.3 5.9 5.4 6.1 2.7 3.1 2.7 2.6 3.0 2.9 392.3 6.0 197.3 3.2 196.6 3.2 126.5 3.4 116.0 3.2 38.1 4.7 63.6 3.1 84.0 2.6 252.2 4.0 274.3 4.0 33.9 8.2 214.7 3.4 110.5 3.7 281.5 5.8 42.0 4.2 200.7 3.4 83.9 2.6 95.1 3.1 45.5 4.5 66.8 4.3 156.6 3.3 68.6 6.6 153.9 4.6' 59.5 5.1 76.8 3.2 41.2 6.7 168.2 2.9 129.8 2.7 1100.5 3.5 136.7 6.1 227.5 5.8 109.5 3.2 1133.3 2.8 !123.1 3.2 67.5 2.7 53.8 2.5 )90.0 4.1 14.8 7.7 198.9 11.7 331.0 7.2 242.1 5.9 376.0 11.7 559.0 10.4 383.4 8.6 153.4 4.3 442.9 9.8 581.9 13.8 331.8 5.9 95.6 4.9 236.9 5.6 155.2 5.4 405.3 9.9 208.3 6.0 P643.8 19.4 748.0 18.8 559.4 11.9 98.1 12.3 1216.2 8.0 1 134.5 5.9 588.6 9.1 5231.1 5.6 7 86.3 11.3 3 173.2 6.5 23.3 15.5 427.6 15.3 1 46.6 21.4 2 101.0 9.3 3 255.8 7.1 4 123.5 6.5 283.7 5.9 i175.5 4.0 150.0 2.8 7 176.7 2.9 8 310.1 4.2 9 312.7 5.0 10 174.5 3.0 11 367.5 5.6 12 302.8 4.7 13 339.9 4.8 14 692.5 10.9 15 413.3 5.7 16 215.3 3.9 17 340.2 5.6 18 410.4 6.6 19 405.2 8.7 20 199.9 5.5 21 142.1 4.9 22 193.8 3.8 23 286.0 4.1 24 133.6 4.0 25 153.9 4.7 26 113.8 5.5 27 185.6 3.8 28 93.4 7.5 29 212.9 4.6 30 399.0 11.1 31 136.7 6.4 32 52.7 13.7 33 129.4 9.2 34 146.2 4.2 2 24.0 3.2 4 313.2 5.1 5 313.3 6.5 6 12.3 5.9 7 593.2 9.0 8 475.1 7.0 9 259.2 3.8 10 108.2 3.1 11 74.4 4.1 12 446.4 6.2 13 191.0 3.4 14 433.2 7.9 15 838.1 13.9 16 200.8 3.5 17 386.4 5.7 18 250.9 5.0 19 238.5 5.8 20 419.3 8.2 21 50.0 9.1 22 290.1 5.6 23 227.0 6.3 24 213.0 3.8 25 179.8 4.5 26 287.4 6.4 27 107.8 4.8 28 184.1 4.5 29 147.9 5.2 t 30 164.3 17.9 131 33.1 13.4 132 76.8 9.9 133 152.7 6.1 134 66.2 9.5 13 180.3 5.7 34 572.9 10.6 3 5 300.4 5.3 3 6 234.1 3.6 3 7 343.3 5.3 3 8 343.6 4.4 3 9 371.5 5.6 3 10 327.5 5.3 3 11 292.0 3.9 3 12 473.5 7.6 3 13 479.7 7.1 3 14 1144.1 16.3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 0 4 04 04 0' 0' 0' 0' 0' 0.

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 1 33 1 34 i I i 2 5 3 5 4 5 5 5 6 5 7 5 8 5 9 5 14 5 1 5 1: 5 1.

5 1.

5 1 5 1 5 1 5 1 5 1 145.5 444.04 633.2 462.2 629.1 132.4 4 269.9 411.6 236.5 293.0 245.6 208.7 266.0 42.5 1.

123.2 351.8 3 175.1 38.0 1 80.9 1 119.7 168.1 479.11 391.4 855.31 411.4 108.2 451.1 4 724.4 1 442.6 188.8 302.7 140.3 318.4 295.5 491.2 553.1 246.9 575.4 61.4 537.5 178.8 232.3 211.2 233 ).5 85.9 201.1 198.5 73.2 4118.2 188.2 114.8 113.2 88.0 97.9 127.3 548.7 248.2 241.6 81.4 211.8 316.5 I699.7 0 404.7 1 491.6 2 251.2 3 373.7 4 478.8 5 370.0 6 418.8 7 679.8 8 336.4 9 224.8 9 .4 6.8 6.7 7.8 4.9 5.9 3.8 4.3 4.6 5.8 10.2 5.1 2.6 5.2 1.4 0.0 5.3 2.7 5.3 6.7 0.9 6.4 3.6 4.7 3.2 5.1 4.6 6.3 8.3 8.7 7.6 7.6 4.1 4.9 5.6 5.8 10.2 13.7 5.2 6.6 8.2 6.8 2.9 2.4 9.7 4.2 2.3 3.6 5.3 9.2 5.8 7.3 4.9 5.7 11.7 7.6 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -105- 0 5 20 351.4 5.7 0 7 25 156.4 3.7 0 9 32 120.8 6.2 0 12 8 166.2 2.8 0 5 21 374.9 6.0 0 7 26 187.7 4.0 0 9 33 27.3 12.0 0 12 9 747.3 11.4 O 5 22 100.2 6.0 0 7 27 69.8 8.7 0 10 1 112.0 2.6 0 12 10 128.8 2.9 0 5 23 200.5 3.9 0 7 28 221.4 4.7 0 10 2 342.2 4.6 0 12 11 311.8 4.6 0 5 24 132.3 4.4 0 7 30 34.7 12.9 0 10 3 403.8 5.4 0 12 12 267.7 3.9 *0 5 25 365.3 6.9 0 7 31 122.0 8.0 0 10 4 298.4 3.9 0 12 13 284.5 5.4 0 5 26 96.4 4.7 0 7 32 66.9 10.1 0 10 5 430.2 6.0 0 12 14 262.0 4.8 0 5 27 219.6 3.9 0 7 33 128.0 5.7 0 10 6 286.9 3.9 0 12 15 64.7 5.9 0 5 28 241.6 4.7 0 8 1 123.8 4.5 0 10 7 236.9 3.8 0 12 16 88.8 4.9 0 5 29 134.2 5.9 0 8 2 660.6 23.4 0 10 8 355.7 7.0 0 12 17 405.3 0 5 31 109.! 7.1 0 8 3 221.8 3.4 0 10 9 200.6 3.4 0 12 18 177.7 5.9 0 5 32 187.1 6.6 0 8 4 473.0 9.0 0 10 10 935.3 14.4 0 12 19 142.7 0 5 33 134.6 6.0 0 8 5 250.2 3.7 0 10 11 593.4 9.3 0 12 20 118.1 0 5 34 94.6 6.4 0 8 6 217.7 2.7 0 10 12 227.4 4.5 0 12 21 171.5 3.8 0 06 1295.8 6.8 0 8 7210.2 3.4 0 10 13232.5 4.8 0 1222 139.8 4.7 0 6 2 530.7 10.2 0 8 8 507.1 7.8 0 10 14 526.9 8.5 0 12 23 187.4 5.1 0 6 3 671.8 13.8 0 8 9 111.7 2.8 0 10 15 668.4 11.6 0 12 24 333.9 0 6 4 835.7 13.4 0 8 10 258.4 4.0 0 1011 6 1185.8 16-.2 0 12 25 129.8 4.1 0 6 5 461.7 6.7- 0 8 11 572.9 8.2 0 10 17 524.3 6.8 0 12 26 194.8 4.3 0 6 6 395.2 6.1 0 8 12 48.9 7.1 0 10 18 259.2 5.4 0 12 27 145.8 0 6 7 508.8 8.5 0 8 13 932.2 15.8 0 10 19 654.9 12.3 0 12 28 86.4 17.3 0 6 8 224.3 4.1 0 8 14 114.9 4.4 0 10 20 291.4 4.7 0 12 29 212.5 5.6 0 6 9 106.5 2.6 0 8 15 247.1 5.8 0 10 21 277.1 4.2 0 12 30 173.9 4.4 0 6 10 436.0 6.3 0 8 16 375.3 6.4 0 10 22 190.6 4.3 0 12 3 1 120.0 7.1 0 6 11 43.0 7.8 0 8 17 492.7 8.0 0 10 23 166.8 3.4 0 12 32 46.4 11.7 0 6 12 418.3 5.8 0 8 18 328.6 5.2 0 10 24 36.5 11.8 0 12 33 94.2 6.4 0 6 13 127.1 3.3 0 8 19 398.6 6.9 0 10 25 158.8 3.9 0 13 2 80.6 2.6 0 6 14 190.3 3.5 0 8 20 166.0 5.0 0 10 26 256.5 4.3 0 13 3 233.1 3.7 0 6 15 386.0 6.6 0 8 21 281.2 4.5 0 10 27 211.2 4.3 0 13 4 326.4 4- '9 0 6 16 495.0 8.1 0 8 22 374.3 5.2 0 10 28 194.1 4.6 0 13 5 278.6 4.6 0 6 17 324.7 7.1 0 8 23 297.9 4.5 0 10 29 250.4 9.7 0 13 6 448.3 5.9 0 6 18 43"5.7 8.8 0- 8 24 412.3 6.4 0 10 30 39.4 14.2 0 13 7 84.3 2.7 0 6 19 465.4 7.6 0 8 25 282.4 4.3 0 10 31 43.6 13.6 0 13 8 609.5 8.1 0 6 20 417.9 7.8 0 8 26 180.7 4.5 0 10 32 96.0 8.7 0 13 9 294.5 0 6 21 238.7 5.9 0 8 27 272.3 5.3 0 10 33 165.8 5.3 0 13 10 331.6 0 6 22 432.5 6.9 0 8 28 94.4 7.8 0 11 2 109.4 2.1 0 13 11 405.3 5.6 0 6 23 200.2 3.9 0 8 29 168.3 13.7 0 11 3 482.9 6.8 0 13 12 508.7 7.3 0 6 24 75.5 6.4 0 8 30 247.5 5.0 0 11 4 106.5 1.8 0 13 13 526.6 0 6 25 63.2 7.7 0 8 31 171.9 5.3 0 11 5 84.9 2.0 0 13 14 187.3 0 6 26 51.9 10.7 0 8 32 112.5 5.6 0 11 6 446.7 7.0 0 13 15 206.2 4.9 0 6 27 113.5 5.5 0 8 33 61.0 10.9 0 11 7 203.8 3.0 0 13 16 175.5 3.6 0 6 28 155.5 5.0 0 9 1 104.8 5.0 0 11 8 431.8 5.9 0 13 17 796.7 14.8 0 6 29 170.8 5.5 0 9 2 565.5 7.9 0 11 9 486.3 6.6 0 13 18 721.0 11.6 0 6 30 62.7 9.9 0 9 3 194.4 3.2 0 11 10 259.8 4.5 0 13 19 293.9 4.7 0 6 31 99.9 6.4 0 9 4 381.3 5.4 0 11 11 688.2 12.0 0 13 20 393.1 6.3 0 6 32 147.7 5.4 0 9 5 215.0 3.6 0 11 12 203.4 3.8 0 13 21 156.7 4.8 0 6 33 67.8 10.8 0 9 6 299.1 4.7 0 11 13 303.9 5.0 0 13 22 192.0 3.7 0 6 34 119.7 5.9 0 9 7 178.3 3.4 0 11 14 645.5 11.2 0 13 23 80.4 0 7 1 422.9 10.1 0 9 8 553.4 9.4 0 11 15 288.8 5.1 0 13 24 194.0 4. 3 0 7 2 437.1 8.0 0 9 9 379.5 7.1 0 11 16 457.7 6.6 0 13 25 234.9 0 7 3 288.9 4.8 0 9 10 374.7 6.9 0 11 17 670.7 10.4 0 13 26 192.7 4.2 0 -7 4 508.6 6.7 0 9 11 501.6 7.6 0 11 18 180.9 4.2 0 13 27 70.3 7.9 0 7 5 202.1 3.1 0 9 12 315.4 5.5 0 11 19 204.8 4.6 0 13 28 334.2 7.4 0 7 6 257.0 3.4 0 9 13 273.1 4.3 0 11 20 198.6 3.8 0 13 29 178.8 4.1 0 7 7 638.4 8.1 0 9 14 444.4 7.0 0 11 21 113.3 4.3 0 13 30 169.7 4.9 0 7 8 49.8 4.0 0 9 15 305.1 5.9 0 11 22 62.4 11.4 0 13 31 269.6 4.7 0 7 9 492.1 6.5 0 9 16 598.9 9.9 0 11 23 167.1 3.5 0 13 32 108.0 6.7 0 7 10 222.3 3.2 0 9 17 366.6 8.9 0 11 24 126.8 4.3 0 14 2 160.8 2.8 0 7 11 506.4 8.1 0 9 18 193.2 3.9 0 11 25 197.7 4.4 0 14 3 302.0 3.7 0 7 12 591.6 9.1 0 9 19 452.4 8.5 0 11 26 74.6 7.2 0 14 4 269.4 3.6 0 7 13 359.0 5.3 0 9 20 306.9 5.5 0 11 27 34.6 11.5 0 14 5 128.3 0 7 14 292.2 5.3 0 9 21 419.9 7.1 0 11 28 22.5 10.2 0 14 6 816.6 12.7 0 7 15 436.7 7.0 0 9 22 325.0 6.4 0 11 30 266.2 4.8 0 14 7 382.5 7.1 0 7 16 387.0 6.0 0 9 23 86.0 5.1 0 11 31 32.8 13.3 0 14 8 392.3 5.4 0 7 17 296.9 4.5 0 9 24 420.0 6.1 0 11 32 94.8 9.7 0 14 9 974.8 13.1 0 7 18 466.4 6.7 0 9 25 109.7 6.2 0 11 33 37.5 12.1 0 14 10 602.7 7.4 0 7 19 188.5 4.5 0 9 26 100.8 4.6 0 12 2 353.0 4.6 0 14 11 532.8 9.1 0 7 20 356.9 6.3 0 9 27 297.8 5.4 0 12 3 419.8 5.7 0 14 12 277.6 4.1 0 7 21 204.7 4.7 0 9 28 160.0 5.6 0 12 4 588.6 7.8 0 14 13 622.6 0 7 22 187.7 5.7 0 9 29 286.4 8.6 0 12 5 374.9 5.0 0 14 14 438.8 6.9 0 7 23 48.1 15.4 0 9 30 201.3 5.0 0 12 6 510.4 7.2 0 14 15 278.2 4.2 0 7 24 275.3 4.4 0 9 31 168.9 4.6 0 12 7 507.4 7.2 0 14 16 476.7 7.9 SUBSTITUTE SHEET (RULE .26) WO 99/10379 WO 9910379PCT/GB98/02542 270.5 4.7 481.3 6.8 232.0 3.9 196.0 4.2 252.1 4.8 260.4 4.6 69.4 7.3 260.5 4.4 217.4 4.4 281.9 5.2 158.4 4.4 21.4 10.7 77.3 6.3 133.2 5.4 308.8 5.1 139.0 4.9 157.0 5.6 522.4 13.4 318.0 4.6 236.2 2.9 202.3 2.9 667.0 9.1 143.3 2.9 735.4 13.6 113.5 2.8 604.0 8.9 273.4 4.2 910.4 12.6 800.3 11.9 419.9 5.6 396.0 5.1 424.1 6.2 179.4 4.7 162.8 3.8 180.9 3.6 165.7 3.6 206.1 3.3 341.8 4.9 237.2 3.9 162.4 3.5 283.2 5.0 195.1 5.4 108.8 5.5 188.1 4.1 153.2 4.6 178.6 4.3 62.6 8.1 178.0 5.3 214.4 2.8 576.5 8.3 176.8 2.6 293.6 4.0 293.0 4.8 176.3 3.0 447.2 6.2 739.5 11.4 241.3 4.0 194.4 3.9 227.7 5.1 200.6 3.7 489.4 7.8 723.9 10.6 123.9 6.1 127.3 6.1 328.2 4.5 131.6 3.8 208.9 4.4 293.4 4.6 115.1 4.6 177.0 6.3 i190.8 4.4 96.8 6.0 27 303.5 9.5 28 163.2 4.4 29 133.0 4.9 30 154.8 4.2 31 163.2 4.7 3 219.1 2.8 4 165.1 2.1 5 842.1 10.8 6 297.6 3.8 7 244.7 4.0 8 860.1 12.1 9 280.2 4.0 10 240.1 5.4 11 218.0 3.9 12 462.1 6.0 13 226.8 3.5 14 271.5 5.1 15 410.7 7.9 16 425.6 6.5 17 417.1 7.5 18 140.8 3.7 19 399.5 6.4 20 172.8 3.6 21 275.3 4.1 22 198.5 3.3 23 70.8 6.4 24 94.0 4.4 25 65.6 6.5 26 87.5 7.9 27 48.8 11.8 28 13.6 6.9 29 95.7 6.0 30 24.0 11.8 31 32.5 12.3 3 543.4 9.0 4 766.4 9.4 5 920.7 11.8 6 1453.7 30.9 7 454.7 6.6 8 318.9 4.3 9 64.1 5.3 10 113.4 2.9 11 105.4 5.1 12 240.7 3.8 13 546.4 7.8 14 332.1 4.7 15 302.0 4.5 16 191.2 3.5 17 342.8 6.2 18 176.7 3.4 19 446.5 6.2 20 110.5 3.6 21 326.1 4.6 22 155.9 3.4 23 217.1 3.7 24 54.3 9.0 25 91.2 6.0 26 170.0 12.1 27 322.4 5.4 28 201.0 4.3 29 160.2 4.8 30 105.8 7.9 31 126.5 5.0 3 619.2 9.5 4 497.9 7.3 5 394.1 4.8 6 296.1 4.1 7 334.2 4.6 P8 425.5 6.4 P9 670.8 8.4 I10 301.4 4.8 11 455.3 6.6 -106- 0 19 0 19 1 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 192 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 20 0 21 0 21 0 21 0 21 0 21 o 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 0 21 260.6 4.7 376.0 5.8 218.6 4.3 334.3 4.7 317.0 4.8 98.0 3.9 139.9 3.3 110.4 4.0 177.7 3.9 252.6 3.7 64.2 5.9 69.4 6.1 159.6 3.5 66.1 6.3 87.1 8.9 98.5 6.1 96.0 7.6 20.6 9.9 200.0 5.0 151.3 6.5 186.4 4.8 452.1 5.5 467.5 6.4 365.0 4.9 431.1 6.0 253.3 3.5 361.8 5.1 168.5 2.8 527.1 8.1 326.5 5.3 107.2 4.0 204.7 5.1 74.3 4.0 200.8 3.7 219.5 3.7 244.0 4.4 197.4 3.3 149.0 3.3 137.9 3.2 42.0 8.3 140.0 3.5 342.3 4.8 128.4 12.0 158.7 4.7 136.6 4.0 255.1 4.7 134.3 4.8 155.5 5.1 67.4 4.5 396.6 5.1 198.8 2.8 100.7 2.3 428.2 5.4 475.2 7.2 408.8 5.2 P493.9 7.6 97.1 3.2 541.0 7.9 14.1 6.8 186.9 3.3 273.6 3.8 183.9 3.2 294.9 4.3 1405.4 5.5 240.0 3.5 272.0 4.0 1278.0 4.1 391.9 5.4 1127,4 5.0 1 90.2 4.7 520.0 9.6 5113.6 4.4 117.8 4.9 123.2 135.0 7.1 73.6 169.9 7.3 324.4 4.9 214.5 3.4 245.2 3.4 700.2 211.1 3.1 477.9 6.8 228.6 3.8 381.8 276.5 368.9 5.7 274.6 4.4 342.6 5.1 497.1 8.4 81.9 3.7 68.3 4.3 224.8 116.5 3.3 101.4 3.7 239.1 3.7 241.5 4.1 309.6 17.9 167.0 105.7 5.9 106.6 6.3 148.7 4.1 56.7 9.3- 223.6 7.6 161.5 2.4 284.5 3.8 227.6 3.2 21.7 7.8 313.0 5.3 244.8 3.6 96.8 2.9 263.6 1123.8 2.7 1 368.1 5.4 i203.3 3.1 i155.8 2.8 1 237.4 4.1 321.6 8.9 )176.1 *96.7 3.7 1 93.0 4.2 1 194.4 3.4 3 126.0 t 293.3 5.6 5 143.0 3.6 5 276.3 4.9 7 26.3 11.7 9 130.7 4.6 S71.4 10.4 *326.6 147.5 2.3 386.9 4.9 1479.0 6.9 0413.2 5.8 0 263.5 1 284.5 2 166.9 3 376.4 4 222.7 3.3 5 240.0 3.6 6 287.5 4.2 7 218.7 3.3 8 203.4 3.3 9 236.5 SUBSTITUTE SHEET (RULE 26) WO 99/1 0379 -107- 107.1 4.3 18.6 8.5 129.6 3.7 239.2 11.9 80.7 5.9 178.6 3.6 78.7 6.5 34.4 11.8 82.3 6.4 456.8 8.3 500.0 7.0 39.2 4.6 234.5 3.3 240.4 3.4 350.5 4.7 395.9 5.9 260.1 4.2 132.8 2.6 111.3 2.9 184.4 3.2 89.0 3.3 145.2 2.9 348.4 5.0 72.1 4~3 103.2 4.1 396.1 7.0 187.8 7.6 187.8 3.6 135.0 4.1 77.3 5.8 175.2 4.0 78.7 6.0 431.3 7.1 427.7 6.4 61.5 3.5 194.6 2.9 137.8 2.3 1374.5 5.4 278.4 3.6 299.8 5.3 48.8 5.8 254.2 4.3 316.8 4.8 142.0 2.9 89.4 4.1 44.2 6.7 276.1 4.0 40.4 10.0 216.7 4.3 80.8 5.9 1211.6 4.2 1184.6 4.4 i122.2 5.3 i220.9 5.0 7179.9 3.9 282.0 5.7 398.6 5.5 500.5 6.2 60.9 2.7 301.8 4.0 )42.7 4.8 1 306.2 4.2 2 254.5 3.6 3 152.0 2.6 4 207.2 3.1 109.4 2.9 291.8 3.8 7 87.4 3.7 8 113.4 3.4 9 253.4 3.8 D 246.5 4.0 1 200.8 4.4 0 27 2 0 27 2 0 27 2 0 27 2 0 28 0 28 0 28 0 28 0 28 0 28 1 0 28 1 0 28 1 0 28 1 0 28 1 0 28 1 0 28 1 0 28 I 0 28 1 0 28 1 0 28 0 28 0 28 0 28 0 28 0 28 0 28 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 29 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 30 0 31 0 31 0 31 0 31 0 31 0 31 0 31 51.0 9.3 135.5 4.0 269.1 4.1 238.1 4.5 9.4 1.8 300.7 5.7 214.0 2.9 394.2 5.2 168.1 2.8 204.0 2.8 122.5 2.5 346.3 4.9 244.2 3.3 243.0 3.5 161.1 3.2 166.6 3.0 150.9 3.2 280.3 5.0 112.5 4.0 158.7 14.7 201.1 3.6 167.1 3.8 107.1 7.4 191.3 4.1 259.7 4.6 46.2 12.0 444.1 10.4 102.1 2.6 264.2 4.0 131.5 2.1 153.9 2.3 93.8 2.4 324.5 4.2 293.7 4.0 186.8 2.8 67.0 3.6 140.6 2.8 234.8 3.7 309.5 5.6 269.1 4.3 328.4 8.6 181.2 3.9 53.8 8.2 126.4 3.7 167.2 7.2 1 123.7 4.3 i151.0 3.9 314.7 5.8 74.2 1.9 137.3 2.0 49.1 3.1 154.4 2.2 1 112.4 2.7 Z145.9 3.0 3111.6 3.0 t 89.0 4.0 5 67.5 5.0 5 67.7 3.8 9 168.5 7.6 135.0 3.3 3 150.9 3.5 1 233.6 4.2 2 180.0 3.7 3 153.8 3.5 4 100.7 5.5 136.4 2.9 149.4 2.1 138.0 4.5 17.6 7.1 0 219.0 3.2 1 240.0 3.1 2 195.7 2.9 0 31 0 31 0 31 0 31 0 31 0 31 0 31 0 31 0 31 0 31 0 31 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 32 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 33 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 34 0 35 0 35 0 35 0 35 0 35 0 35 0 35 0 35 0 35 0 31 0 35 0 35 13 178.7 14 98.6 I5 251.7 16 91.1 17 419.0 18 141.2 19 248.3 20 59.0 21 148.3 22 91.4 23 114.4 4 4.21 6 126.7 7 53.52 8 294.4 9 183.7 10 246.7 11 171.9 12 455.1 13 264.9 14 53.0 15 69.6 16 228.7 17 103.4 18 187.3 19 124.9 20 274.5 21 124.8 22 89.2 7 176.4 8 235.2 9 93.3 10 117.2 11 53.5 12 42.9 13 136.8 14 204.8 15 263.3 16 40.7 17 257.9 18 205.1 19 177.3 20 100.7 21 115.2 22 207.7 7 120.0 8 56.5 9 29.8 10 159.6 11 25.8 12 190.7 13 285.2 14 24.2 15 233.3 16 117.0 17 209.3 18 66.1 19 155.5 20 270.8 21 45.7 6 16.1 7 157.9 8 50.3 9 219.6 10 139.2 11 326.3 12 187.9 13 305.9 314 212.0 315 39.3 5 16 112.8 5 17 95.0 2.9 3.0 3.4 5.3 6.6 4.1 5.1 5.9 3.4 4.8 3.9 .5 3.6 3.7 2.5 3.3 2.7 6.3 3.5 6.3 9.6 4.2 3.8 3.9 4.8 4.4 3.6 4.9 3.8 3.5 2.1I 2.4 3.4 5.5 3.1 5.4 4.1 7.3 3.9 3.7 3.6 4.2 4.1 4.7 2.5 2.5 6.3 3.2 7.8 7.1 4.7 8.7 3.6 3.9 3.7 5.4 3.6 4.3 15.2 5.1 4.1 3.7 3.5 6.1 5.6 3.1 4.5 3.5 7.4 3.4 3.6 PCT/GB98/02542 35 18 151.4 3.4 35 19 62.4 5.8 36 7 85.5 36 8 230.0 6.3 36 9 71.6 3.6 36 10 57.6 3.3 36 11 65.7 D 36 12 142.2 2.7 D 36 13 178.5 3.2 D 36 14 134.2 2.8 D 36 15 58.0 5.2 D 36 16 105.0 0 36 17 164.1 D 36 18 39.3 10.1 0 37 8 133.9 4.4 0 37 9 102.4 2.4 0 37 10 245.5 0 37 11 144.4 2.4 0 37 12 234.5 3.9 0 37 13 142.0 3.2 0 37 14 170.8 0 37 15 136.6 2.9 0 37 16 87.9 3.8 0 37 17 12.4 6.1 0 38 8 55.1 0 38 9 163.7 3.7 0 38 10 27.9 6.4 0 38 11 83.7 2.9 0 38 12 70.0 4.2 0 38 13 70.7 0 38 14 110.5 0 38 15 111.9 2.8 0 38 16 148.9 4.7 0 39 9 176.8 3.9 0 39 10 146.9 0 39 11 61.4 3.1 0 39 12 66.3 3.8 0 39 13 90.5 2.8 0 39 14 132.0 3.7 0 40 9 75.6 4.1 0 40 10 205.6 4.3 0 40 11 247.1 4.2 0 40 12 151.0 0 41 9 241.2 8.9 0 41 10 30.9 8.3 1 0 2 30.3 1 0 4 415.9 11.0 1 0 5 110.9 3.8 1 0 6 646.2 14.3 1 0 7 506.8 14.4 1 0 8 147.7 4.6 1 0 9 147.2 4.1 1 0 10 93.7 4.8 1 0 11 560.0 12.9 I 0 12 58.9 9.1 1 0 13 10.4 7.7 1 0 14 324.3 6.1 1 0 15 150.4 5.7 1 0 16 390.5 7.7 1 0 17 216.0 14.5 1 0 18 518.6 1 0 19 44.9 22.0 1 0 20 114.7 6.2 1 0 21 193.7 1 0 22 375.3 8.3 1 0 23 70.4 15.7 1 0 24 396.2 8.3 1 0 25 118.3 6.6 1 0 26 146.2 5.9 1 0 27 96.5 9.4 1 0 28 98.8 10.6 1 0 29 56.6 15.8 SUBSTITUTI SHEET (RULE 26) WO 99/10379 -108o 30 166.9 .15.6 o 31 69.5 18.4 o 32 81.2 17.8 o 33 41.7 19.9 0 34 19.3 14.1 1 2 18.8 3.4 1 4 341.3 6.3 1 5 481.3 8.0 1 6 250.5 5.0 1 7 219.9 4.0 1 8 382.9 5.5 1 9 265.6 4.0 1 10 69.8 3.6 1 11 182.4 3.1 1 12 170.6 3.1 1 13 545.9 7.4 1 14 219.4 3.5 1 15 381.2 4.8 '1 16 133.0 4.0 1 17 252.9 7.7 1 18 273.5 7.1 1 19 103.0 5.2 1 20 263.2 4.9 1 21 551.6 7.8 1 22 284.0 4.7 1 23 214.7 4.3 1 24 286.6 5.3 1 25 161.5 4.3 1 26 147.3 4.0 1 27 43.9 11.7 1 28 31.1 13.2 1 29 115.0 6.7 1 30 169.6 7.8 1 31 104.6 10.0 1 32 96.7 8.4 1 33 79.1 9.4 1 34 222.4 5.2 2 0 18.3 7.1 2 1 17.4 5.0 2 4 300.5 5.5 2 5 489.7 8.5 2 6 328.6 6.4 2 7 137.1 2.3 2 8 176.2 3.3 2 9 378.8 5.4 2 10 470.4 7.3 2 11 187.9 3.2 2 12 573.5 7.9 2 13 373.6 5.4 2 14 20.0 8.9 2 15 167.2 4.0 -2 16 299.6 4.5 2 17 505.7 7.4 2 18 497.4 6.8 2 19 127.5 4.5 2 20 242.2 4.5 2 21 221.8 6.4 2 -22 269.9 4.9 2 23 55.0 14.2 2 24 180.7 4.0 2 25 144.4 3.9 2 26 317.1 4.7 2 27 72.0 7.3 2 28 198.7 4.6 2 29 158.9 4.1 2 30 23.8 12.0 2 31 123.3 6.4 2 32 92.0 8.7 2 33 101.7 6.9 2 34 155.2 6.4 3 2 72.5 3.7 3 3 231.8 5.8 3 4 449.3 8.4 3 5 450.5 7.1 3 6 613.1 10.0 3 7 589.7 8.5 3 8 27.6 8.3 3 9 537.7 8.3 3 10 457.3 6.8 3 11 202.6 3.1 3 12 313.1 4.2 3 13 651.2 9.3 3 14 414.8 5.9 3 15 78.7 4.5 3 16 168.1 4.0 3 17 474.1 7.6 3 18 346.4 5.9 3 19 211.5 4.2 3 20 132.2 5.2 3 21 123.9 6.1 3 22 119.7 4.9 3 23 230.5 5.1 3 24 86.3 6.1 3 25 107.0 5.6 3 26 102.6 5.0 3 27 127.6 4.7 3 28 141.7 6.1 3 29 66.1 9.1 3 31 150.9 5.4 -3 32 65.7 12.6 3 33 190.6 4.7 3 34 60.8 13.4 4 2 294.9 10.9 4 3 134.9 3.1 4 4 442.5 7.1 4 5 510.3 9.3 4 6 168.8 3.2 4 7 428.6 6.4 4 8 227.9 3.3 4 9 99.7 2.7 4 10 95.5 3.2 4 11 154.0 3.0 4 12 184.0 3.2 4 13 278.1 4.1 4 14 429.6 6.0 4 15 396.4 6.0 4 16 498.6 7.4 4 17 426.9 6.6 4 18 330.7 6.2 4 19 429.5 6.7 4 20 367.5 5.7 4 21 608.7 8.1 4 22 236.9 4.4 4 23 284.0 5.8 4 24 93.4 5.7 4 25 237.3 4.1 4 26 251.4 6.2 4 27 245.9 4.2 4 28 144.5 4.8 4 29 44.4 12.6 4 30 126.4 7.2 4 32 92.4 9.1 4 33 126.5 6.0 4 34 80.6 13.1 5 0 137.6 5.2 5 1 225.4 5.6 5 3 390.2 6.9 5 4 737.6 18.9 5 5 425.1 6.6 5 6 257.4 4.3 5 7 453.7 6.5 5 8 333.4 4.5 5 9 374.3 5.3 5 10 298.2 4.2 5 11 336.8 5.1 5 12 174.5 3.2 5 13 477.7 6.3 5 14 555.1 7.2 5 15 191.4 3.7 5 16 689.9 10.9 5 17 208.3 5.0 5 18 368.3 5.5 5 19 295.0 5.5.

5 20 274.7 4.4 5 21 380.0 5.5 5 22 290.6 5.8 5 23 109.2 5.1 5 24 91.3 5.0 5 25 156.9 4.8 5 26 96.5 6.2 5 27 87.9 6.4 5 28 156.1 4.7 5 29 91.6 12.8 5 30 27.1 12.4 5 31 40.5 14.0 5 32 241.2 5.8 5 33 235.3 5.0 5 34 82.2 10.6 6 0 300.2 8.6 6 1 426.1 7.8 6 2 186.6 2.9 6 3 648.5 26.2 6 4 241.7 4.7 6 5 839.5 14.0 6 6 628.9 8.3 6 7 389.7 5.6 6 8 451.3 6.9 6 9 338.6 5.2 6 10 97.3 3.1 6 11 212.8 3.4 6 12 371.8 5.5 6 13 690.0 10.0 6 14 446.0 6.1 6 15 708.7 8.6 6 16 353.2 5.3 6 17 196.4 4.1 6 18 323.0 4.8 6 19 307.8 4.9 6 20 188.0 4.0 6 21 173.7 4.2 6 22 268.0 4.5 6 23 208.5 4.5 6 24 149.4 4.6 6 25 243.8 4.1 6 26 155.5 3.9 6 27 23.4 10.5 6 28 135.4 4.9 6 30 74.8 9.4 6 31 60.5 13.7 6 32 91.4 9.1 6 33 232.0 4.8 7 0 212.9 4.8 7 1 160.1 3.0 7 3 84.9 1.8 7 4 97.2 1.9 7 5 315.8 4.3 7 6 168.5 2.8 7 7 103.7 2.1 7 8 362.5 5.0 7 9 136.0 2.6 7 10 537.5 7.2 7 11 407.2 6.5 7 12 126.3 3.6 7 13 306.8 4.3 7 14 921.2 12.8 7 15 463.0 6.2 PCT/GB98/02542 1 7 16 214.2 7.8 I 7 17 665.7 9.2 1 7 18 313.9 1 7 19 390.6 5.9 1 7 20 142.9 4.3 I 7 21 172.6 4.9 1 7 22 124.6 I 7 23 230.6 1 7 24 125.6 1 7 25 177.2 5.2 I 7 26 222.0 I 7 27 66.3 9.3 1 7 28 150.1 4.4 I 7 29 162.8 16.3 1 7 30 58.0 13.1 I 7 31 101.0 9.8 I 7 32 147.5 5.8 1 7 33 147.9 1 8 0 359.8 11.7 1 8 1 436.8 8.9 1 8 2 627.0 8.1 1 8 3 509.4 8.3 1 8 4 298.8 4.4 1 8 5 223.2 1 8 6 311.8 1 8 7 654.5 9.4 1 8 8 253.1 1 8 9 143.4 2.7 1 8 10 613.5 1 8 11 159.8 1 8 12 785.7 12.1 1 8 13 335.3 1 8 14 272.1 1 8 15 532.4 7.7 1 8 16 211.7 6.1 1 8 17 430.5 6.3 1 8 18 262.1 4.9 I 8 19 763.8 11.8 1 8 20 245.2 1 8 21 255.6 1 8 22 210.2 4.1 1 8 23 280.5 4.3 1 8 24 94.2 5.3 1 8 25 215.3 4.7 1 8 26 206.4 4.2 I 8 27 183.7 4.7 1 8 28 148.0 7.3 1 8 29 413.4 12.4 1 8 30 49.8 13.8 1 8 31 185.9 4.7 1 8 32 24.4 11.2 1 9 0 303.7 1 9 1 206.1 2.7 1 9 2 103.8 1 9 3 572.2 1 9 4 316.1 4.3 1 9 5 83.7 1 9 6 372.0 1 9 7 432.7 5.7 1 9 8 560.3 7.3 1 9 9 415.4 1 9 10 602.8 8.9 1 9 11 430.6 5.7 1 9 12 616.1 8.3 1 9 13 113.1 4.1 1 9 14 454.7 7.3 1 9 15 199.7 4.1 1 9 16 113.3 5.4 1 9 17 442.9 6.2 1 9 18 394.5 5.9 1 9 19 110.8 5.1 1 9 20 386.6 5.6 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -109- 21 22 23 24 26 27 28 29 31 32 33 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 P22 P23 I24 26 27 12 1 30 31 .2 .3 .4 1 5 [16 1 7 1 8 1 9 1 2( 1 12 1 2: 1 1' 1 1: 1 2~ 1 2 1 2 233.8 81.4 6 90.8 5 69.5 6 73.7 6 209.0 285.4 170.1 153.3 1 123.0 166.9 130.9 '49.4 155.4 142.5 235.7 181.8 353.2 371.8 .354.6 535.5 67.83 141.4 113.9 850.4 577.1 139.2 778.3 509.3 382.0 394.2 198.3 P408.9 337.7 175.1 150.4 20.7 244.5 212.5 103.2 52.8 120.8 308.3 157.4 192.3 1158.2 202.9 195.0 85.0 220.3 347.6 533.8 235.8 16.8 )125.4 1 287.6 2 487.5 3 589.5 4 687.7 5 184.0 6 131.0 7 373.0 8 183.7 9 258.4 0 69.0 1 138.1 2 248.5 3 205.6 4 227.5 240.5 6 122.4 7 18.9 4.

.4 '.2 .9 .3 5.5 4.7 5.3 4.7 7.9 4.8 6.3 5.2 2.0 2.2 3.4 2.5 5.' 6.0 4.8 7.6 1.5 2.8 3.2 11.8 9.0 3.6 11.9 8.8 5.7 7.2 4.2 5.9 5.0 4.1 3.9 10.1 4.4 4.5 6.2 11.5 9.1 4.9 5.4 4.9 6.3 2.7 2.5 1.9 3.5 4.4 6.7 3.3 7.9 3.2 4.6 6.6 8.5 10.5 3.8 6.7 6.2 4.3 4.5 7.6 6.2 4.5 5.4 4.1 4.1 4.3 9.3 28 206.4 4.7 29 252.3 4.8 30 177.9 4.7 31 139.8 6.9 32 37.9 13.3 33 130.4 6.6 0 155.0 5.5 1 222.3 2.8 2 579.6 7.1 3 165.6 2.1 4 613.3 8.6 5 717.8 9.2 6 145.7 2.3 7 602.4 8.0 8 540.6 8.5 9 326.2 4.9 10 476.6 8.6 11 415.0 5.4 12 221.5 3.5 13 179.2 3.4 14 426.1 6.0 15 89.7 5.0 16 474.5 6.5 17 449.4 6.5 18 292.5 4.4 19 53.5 9.7 20 225.0 3.9 21 170.3 4.7 22 232.8 4.3 23 70.2 6.0 24 164.6 4.4 25 124.0 4.3 26 26.4 10.9 27 78.9 7.7 28 134.1 22.2 29 243.5 4.4 30 89.1 7.7 31 377.6 5.5 32 76.9 9.1 1 116.1 2.2 2 580.5 8.2 3 172.3 2.4 4 234.3 3.2 5 374.4 5.4 6 807.9 11.4 7 678.6 9.8 8 549.4 7.5 9 980.2 14.0 10 504.0 6.5 11 71.3 3.8 12 195.0 3.1 13 250.7 4.3 114 244.9 4.1 115 420.9 6.0 1 16 162.8 4.0 1 17 96.5 6.7 118 199.1 4.6 119 217.6 3.7 120 382.9 6.2 121 291.3 4.4 1 22 171.6 5.0 1 23 73.0 7.5 3 24 26.4 10.9 3 25 80.3 7.4 3 26 119.8 5.3 3 27 106.8 5.5 3 28 274.8 20.2 3 29 111.0 5.5 3 30 26.2 12.2 3 31 255.0 5.0 3 32 32.1 14.1 4 1 356.1 9.1 2 304.6 4.3 3 205.6 2.5 4 174.7 2.5 5 374.2 4.7 6 394.4 5.6 7 267.2 3.3 8 301.0 4.3 9 403.5 5.9 10 69.1 4.5 11 313.0 4.4 12 480.7 7.0 13 172.0 5.0 14 214.5 4.2 15 476.7 7.0 16 235.1 4.0 17 244.1 4.4 18 255.6 4.3 19 272.8 4.5 20 158.1 4.4 21 187.8 3.8 22 73.7 7.0 23 203.9 4.1 24 120.6 4.5 25 15.9 7.9 26 68.1 6.8 27 359.5 5.3 28 103.6 6.8 29 29.5 11.8 30 173.3 7.2 31 148.3 6.2 32 238.9 4.9 1 474.1 11.6 2 522.7 6.4 3 580.5 7.6 4 580.1 7.5 5 141.5 2.1 6 221.8 3.0 7 268.3 3.4 8 361.1 4.8 9 569.7 7.9 10 417.9 6.0 11 230.3 3.7 12 403.4 5.9 13 356.9 5.0 14 334.0 5.3 15 201.7 3.5 16 239.1 4.2 17 337.7 6.1 18 241.9 4.0 19 198.3 3.6 20 78.0 5.8 21 200.1 3.6 22 98.0 5.5 23 435.2 6.9 24 21.4 9.6 25 110.6 4.3 26 75.0 6.9 27 110.4 15.6 28 313.8 5.5 29 234.7 4.4 30 133.9 5.7 i31 131.5 6.3 i32 102.3 11.4 i2 327.7 5.2 i3 224.7 3.1 i4 55.9 2.6 S5 891.5 12.4 3 6 181.5 2.5 5 7 253.9 3.8 5 8 155.0 2.5 5 9 483.7 7.6 5 10 337.7 4.9 11 667.1 8.8 12 198.9 4.1 13 433.6 5.8 14 270.6 4.8 15 321.0 6.4 16 288.2 4.8 17 47.4 10.6 18 103.3 5.4 19 340.5 20 199.6 3.8 21 253.4 4.1 22 274.4 5.2 23 327.6 4.8 24 169.6 4.3 25 272.9 26 119.1 4.7 27 203.8 13.4 28 104.6 5.3 29 148.0 5.1 30 60.4 11.6 31 233.3 2 418.6 9.4 3 268.1 3.4 4 320.7 4.1 5 933.0 14.9 6 306.5 4.3 7 92.2 2.8 8 419.9 5.8 9 409.1 5.9 10 277.4 4.7 11 275.6 12 478.4 7.1 13 295.8 14 306.0 4.3 15 222.9 4.3 16 348.6 6.2 17 279.4 4.4 18 178.5 4.3 19 85.4 4.6 20 165.0 3.9 21 237.4 3.9 22 137.6 4.6 23- 172-:3- 24 159.6 3.8 25 113.0 4.7 26 13.6 6.9 27 100.6 5.9 28 34.3 12.5 29 217.0 4.6 30 121.4 31 133.6 2 450 .3 12.0 3 301.9 4.3 4 530.9 7.1 5 862 .6 10.9 6 661.1 9.2 7 1110.7 14.9 18 513 .5 8.2 19 406 .4 6.1 110 534.2 7.2 1 11 134.4 7.9 112 183.5 113 274.2 4.3 1 14 163.0 4.4 3 15 471.2 6.8 3 16 34.1 10.5 3 17 419.1 5.7 3 18 14.8 9 19 152.2 4.2 9 20 188.9 3.6 8 21 277.2 4.8 8 22 426.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -110- I 18 23 113.9 5.4 1 21 9 593.9 8.2 1 23 27 78.8 7.1 1 26 25 144.1 4.8 1 18 24 172.4 4.8 1 21 10 351.1 4.7 1 23 28 173.2 4.2 1 26 26 69.8 7.3 1 18 25 265.7 4.5 1 21 11 370.2 5.7 1 24 3 258.5 6.1 1 26 27 59.1 9.3 1 18 26 286.1 9.0 1 21 12 209.0 3.3 1 24 4 543.6 10.1 1 27 5 285.7 4.1 1 18 27 212.1 4.4 1 21 13 180.3 3.6 1 24 5 153.8 2.3 1 27 6 137.6 1.9 1 18 28 208.8 4.2 1 21 14 125.7 3.7 1 24 6 66.5 2.5 1 27 7 203.0 2.7 1 18 29 79.1 7.1 1 21 15 176.2 3.9 1 24 7 550.6 7.8 I 27 8 129.6 2.8 1 18 30 211.7 4.3 1 21 16 132.2 3.2 1 24 8 49.1 3.9 1 27 9 97.9 2.2 1 18 31 26.3 12.2 1 21 17 138.8 3.6 1 24 9 297.4 3.9 1 27 10 354.9 4.9 1 19 1 66.1 2.8 1 21 18 184.8 3.3 1 24 10 357.4 7.2 1 27 11 227.3 3.3 1 19 3 282.3 3.4 1 21 19 295.2 4.3 1 24 11 261.6 3.7 1 27 12 234.2 4.3 1 19 4 809.4 11.1 1 21 20 241.4 3.9 1 24 12 154.9 2.7 1 27 13 220.5 3.6 1 19 5 452.2 6.4 1 21 21 172.7 3.2 1 24 13 235.7 3.3 1 27 14 374.9 1 19 6 835.7 11.5 1 21 22 167.5 3.6 1 24 14 215.3 3.2 1 27 15 209.1 3.3 1 19 7 407.6 5.6 1 21 23 132.7 5.3 1 24 15 172.0 2.9 1 27 16 387.7 5.6 1 19 8 432.7 6.9 1 21 24 103.4 5.2 1 24 16 103.3 3.2 1 27 17 78.2 4.1 1 19 9 555.6 9.0 1 21 25 109.4 5.7 1 24 17 133.1 3.8 1 27 18 311.4 4.6 1 19 10 566.1 8.1 1 21 26 81.8 6.5 1 24 18395.6 5.4 1 27 19190.0 3.4 1 19 11 351.6 5.2 1 21 27 55.0 8.8 1 24 19 407.9 5.6 1 27 21 245.2 4.1 1 19 12 235.2 3.6 1 21 28 193.8 6.2 1 24 20 95.5 3.9 I 27 22 123.6 1 19 13 149.9 3.3 1 21 29 180.8 4.4 1 24 21 192.2 3.4 1 27 23 59.8 11.2 1 19 14 318.8 5.6 1 22 3 211.7 5.3 1 24 22 417.8 6.1 1 27 24 63.8 7.9 1 19 15 98.5 5.0 1 22 4 443.6 6.4 1 24 23 211.6 6.4 1 27 25 178.0 3.9 1 19 16 264.2 5.0 1 22 5 206.8 3.5 1 24 24 130.6 4.2 I 27 26 226.0 4.1 1 19 17 420.5 7.3 1 22 6 146.7 2.6 1 24 25 264.5 4.5 1 28 4 205.3 4.6 1 19 18 417.1 7.3 1 22 7 714.7 10A4 1 24 26 53.2 11.5 1 28 5 158.6 4.4 1 19 19 546.7 8.5 1 22 8 358.1 5.0 1 24 27 131.2 4.8 1 28 6 154.7 2.3 1 19 20 116.7 3.6 1 22 9 333.2 4.9 1 24 28 146.4 4.8 1 28 7 212.9 2.8 1 19 21 14.6 7.2 1 22 10 474.9 6.7 1 25 4 126.9 4.1 1 28 8 218.4 2.9 1 19 22 198.3 3.7 1 22 11 271.9 3.8 1 25 5 22.1 7.7 1 28 9 302.1 4.1 1 19 23 58.7 8.4 1 22 12 294.6 4.6 1 25 6 134.3 2.3 1 28 10 284.0 3.8 1 19 24 74.6 5.6 1 22 13 233.5 3.8 1 25 7 432.6 7.2 1 28 11 135.6 2.8 1 19 25 80.6 6.7 1 22 14 138.8 3.2 1 25 8 136.5 2.9 1 28 12 172.2 2.7 1 19 26 71.5 8.4 1 22 15 131.6 3.0 1 25 9 429.7 6.6 1 28 13 151.6 2.7 1 19 27 39.9 13.0 1 22 16 89.9 3.8 1 25 10 363.6 6.1 1 28 14 234.3 3.4 1 19 28 106.1 5.4 1 22 17 244.8 3.7 1 25 11 84.4 3.4 1 28 15 297.9 4.7 1 19 29 19.6 9.3 1 22 18 151.0 3.3 1 25 12 434.1 7.5 1 28 16 72.7 1 19 30 107.0 6.4 1 22 19 72.9 4.7 1 25 13 12.5 6.2 1 28 17 102.8 3.3 1 20 1 17.3 0.6 1 22 20 69.0 5.8 1 25 14 594.5 7.9 1 28 18 113.9 3.2 1 20 3 517.3 7.5 1 22 21 76.0 6.3 1 25 15 222.2 3.5 1 28 19 18.8 1 20 4 53.7 2.8 1 22 22 173.1 3.5 1 25 16 385.4 5.7 1 28 20 204.8 3.7 1 20 5 482.7 6.0 1 22 23 130.0 4.2 1 25 17 158.5 3.0 1 28 21 75.7 5.8 1 20 6 756.1 10.2 1 22 24 462.6 9.2 1 25 18 267.2 4.3 1 28 22 106.7 4.1 1 20 7 272.6 3.9 1 22 25 170.7 4.1 1 25 19 218.9 4.3 1 28 23 105.6 1 20 8 250.1 5.3 1 22 26 300.7 4.9 1 25 20 131.2 3.6 1 28 24 128.4 3.7 1 20 9 353.9 6.2 1 22 27 35.1 13.7 1 25 21 217.5 3.4 1 28 25 184.6 5.1 1 20 10 144.2 3.2 1 22 28 121.0 5.3 1 25 22 233.4 9.0 1 29 6 259.1 3.6 I 20 11 243.2 4.2 1 22 29 59.4 8.5 1 25 23 86.7 4.6 1 29 7 '270.6 1 20 12 204.5 3.6 1 23 2 239.0 8.8 1 25 24 130.4 4.1 1 29 8 33.1 4.4 1 20 13 573.1 9.3 1 23 4 268.4 4.1 1 25 25 212.4 4.1 1 29 9 95.2 2.3 1 20 14 488.7 9.2 1 23 5 653.9 8.6 1 25 26 207.7 4.1 1 29 10 269.0 3.9 1 20 15 439.9 6.8 1 23 6 554.0 7.2 1 25 27 228.0 5.3 1 29 11 177.9 2.7 1 20 16 167.7 3.4 1 23 7 170.4 2.7 1 26 5 790.6 14.9 1 29 12 202.1 2.8 1 20 17 454.9 7.3 1 23 8 64.6 3.9 1 26 6 244.8 3.8 1 29 13 98.6 2.9 1 20 18 130.0 3.6 1 23 9 406.3 5.8 1 26 7 367.7 5.4 1 29 14 15.3 7.1 1 20 19 231.2 4.7 1 23 10 86.1 3.4 I 26 8 88.8 2.4 1 29 15 341.3 1 20 20 100.7 5.4 1 23 11 323.9 4.3 1 26 9 113.6 2.7 1 29 16 294.8 5.1 1 20 21 214.6 3.8 1 23 12 212.8 3.1 1 26 10 254.2 3.8 1 29 17 172.3 1 20 22 298.9 4.4 1 23 13 236.8 3.4 1 26 11 222.4 3.0 1 29 18 59.3 7.6 1 20 23 94.2 5.5 1 23 14 230.7 3.6 1 26 12 317.2 4.8 1 29 19 92.4 10.9 1 20 24 170.0 4.3 1 23 15 123.8 3.2 1 26 13 404.9 6.6 1 29 20 162.1 3.3 1 20 25 228.8 8.7 1 23 16 301.7 5.0 1 26 14 218.2 3.2 1 29 21 189.3 4.2 1 20 26 171.5 4.2 1 23 17 409.2 5.3 1 26 15 266.6 4.8 1 29 22 349.4 I 20 27 65.7 10.1 1 23 18 60.4 5.8 1 26 16 237.1 3.6 1 29 23 101.5 4.6 1 20 28 99.1 5.4 1 23 19 263.7 4.0 1 26 17 31.8 7.8 1 29 24 95.4 1 20 29 170.1 5.7 1 23 20 145.0 3.7 1 26 18 229.5 3.5 1 29 25 180.3 5.6 1 20 30 134.1 4.8 1 23 21 237.2 3.6 1 26 19 164.6 3.7 1 30 5 302.2 7.9 1 21 4 652.4 9.1 1 23 22 117.0 3.8 1 26 20 136.3 3.5 1 30 6 264.8 1 21 5 301.3 4.0 1 23 23 195.6 4.9 1 26 21 111.5 7.9 1 30 7 281.1 3.7 1 21 6 96.7 3.0 1 23 24 37.3 11.4 1 26 22 86.7 6.1 1 30 8 273.8 1 21 7 150.1 3.7 1 23 25 116.3 4.7 1 26 23 123.3 4.4 1 30 9 69.8 2.8 1 21 8 438.2 6.0 1 23 26 167.1 4.5 1 26 24 280.8 4.9 1 30 10 155.0 2.4 SUBSTnTUT SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 1 30 11 169.3 2.8 1 34 14 190.5 3.2 2 0 11 86.7 3.9 2 2 19 115.1 5.4 1 30 12 122.9 3.1 1 34 15 102.3 3.1 2 0 12 367.4 8.9 2 2 20 371.7 1 30 13 264.7 3.8 1 34 16 268.5 4.3 2 0 13 608.7 13.3 2 2 21 193.0 4.7 1 30 14 90.6 3.4 1 34 17 141.1 3.8 2 0 14 664.7 16.0 2 2 22 185.1 4.4 1 30 15 192.1 3.7 1 34 18 97.6 3.9 2 0 15 414.4 8.3 2 2 23 376.9 6.1 1 30 16 70.0 4.2 1 34 19 130.9 3.3 2 0 16 523.0 11.1 2 2 24 122.9 5.4 1 30 17 22.8 9.5 1 34 20 46.6 10.3 2 0 17 453.3 10.0 2 2 25 275.4 4.4 1 30 18 106.4 6.1 1 35 5 14.9 2.8 2 0 18 204.4 9.0 2 2 26 296.0 4.8 1 30 19 78.0 4.6 1 35 7 99.8 3.6 2 0 19 120.2 7.5 2 2 27 187.3 4.1 1 30 20 123.1 3.8 1 35 8 127.1 2.8 2 0 20 683.4 14.2 2 2 28 115.1 5.4 1 3 0 21 186.9 3.6 1 35 9 151.8 3.8 2 0 21 248.2 6.7 2 2 29 52.9 15.2 1 30 22 180.7 3.7 1 35 10 281.4 7.5 2 0 23 95.8 15.7 2 2 30 218.4 5.2 1 3 0 23 53.2 7.2 1 35 11 159.5 3.8 2 0 24 61.8 19.5 2 2 31 179.6 6.3 1 30 24 83.4 5.5 1 35 12 140.0 2.8 2 0 25 355.1 8.8 2 2 32 106.6 8.2 1 3 1 6 83.3 3.9 1 35 13 144.5 3.0 2 0 26 94.2 10.3 2 2 33 219.2 5.1 1 31 7 249.7 4.1 1 35 14 76.3 3.7 2 0 27 30.7 17.2 2 2 34 102.1 12.6 1 31 8 249.9 3.9 1 35 15 170.4 3.1 2 0 28 15.8 11.2 2 3 1 228.4 1 31 9 88.0 2.2 1 35 16 88.2 5.1 2 0 29 20.5 13.9 2 3 2 89.9 1.9 1 31 10 239.9 3.5 1 35 17 136.1 3.9 2 0 30 209.0 8.6 2 3 3 352.2 1 31 11 506.8 6.4 1 35 18 16.4 7.7 2 0 31 180.6 7.5 2 3 4 562.7 13.3 1 31 12 212.7 3.2 1 35 19 173.0 3.4 2 0 32 222.1 7.2 2 3 5 497.2 9.6 1 31 13 124.4 2.5 1 36 8 120.5 5.4. 2 0 33 259.7 7.9 2 3 6 579.0 11.2 1 31 14 137.0 2.7 1 36 9 36.2 5.4 2 0 34 16.1 12.0 2 3 7 224.9 3.9 1 31 15 173.8 3.0 1 36 10 115.3 2.6 2 1 3 55.2 2.5 2 3 8 361.8 5.1 1 31 16 97.0 4.4 1 36 11 179.6 3.3 2 1 4 325.8 6.0 2 3 9 742.8 11.3 1 31 17 189.4 3.6 1 36 12 97.7 2.7 2 1 5 241.3 4.3 2 3 10 250.5 3.6 1 31 18 181.0 3.3 1 36 13 81.4 3.4 2 1 6 189.6 3.3 2- 3 11 324.3 4.4 1 31 19 22.1 9.4 1 36 14 116.8 3.6 2 1 7 224.1 3.5 2 3 12 319.8 4.2 1 31 20 14.0 7.0 1 36 15 264.0 4.2 2 1 8 144.4 2.7 2 3 13 54.0 5.2 1 31 21 127.0 3.9 1 36 16 122.0 3.1 2 1 9 413.8 5.5 2 3 14 201.1 3.4 1 31 22 80.4 5.7 1 36 17 101.7 3.4 2 1 10 139.6 2.8 2 3 15 662.4 9.7 1 31 23 80.9 6.6 1 36 18 52.0-- 6.6 2 1- 11 446.7 6.4 2 3 16 249.6 3.9 1 32 6 99.9 3.5 1 37 8 203.8 8.7 2 1 12 234.3 3.8 2 3 17 263.1 4.1 1 32 7 211.3 3.9 1 37 9 94.8 1.9 2 1 13 295.4 4.3 2 3 18 226.4 4.6 1 32 8 71.2 2.2 1 37 10 127.4 3.2 2 1 14 677.0 8.5 2 3 19 186.8 4.6 1 32 9 76.0 2.9 1 37 11 118.2 2.6 2 1 15 273.6 4.2 2 3 20 223.1 1 32 10 138.4 2.5 1 37 12 209.0 4.2 2 1 16 274.7 4.4 2 3 21 154.3 5.2 1 32 11 108.8 2.9 1 37 13 158.1 3.0 2 1 17 278.8 4.7 2 3 22 111.1 5.1 1 32 12 205.3 3.3 1 37 14 135.6 3.1 2 1 18 279.5 5.6 2 3 23 121.8 4.7 1 32 13 150.1 2.8 1 37 15 140.7 3.0 2 1 19 308.8 4.6 2 3 24 16.4 8.3 1 32 14 95.9 3.2 1 37 16 38.9 8.7 2 1 20 113.8 5.6 2 3 25 167.7 4.3 1 32 15 354.7 6.3 1 37 17 146.0 3.6 2 1 21 286.4 4.5 2 3 26 217.8- 4.1 1 32 16 97.1 3.6 1- 38 6 17.7 2.5 2 1 22 137.5 4.4 2 3 27 120.3 4.9 1 32 17 105.1 3.4 1 38 8 172.5 5.1 2 1 23 79.4 7.9 2 3 28 65.5 1 32 18 -324.7 5.3 1 38 9 295.6 5.3 2 1 24 322.9 4.6 2 3 29 107.5 8.4 1 32 19 139.6 3.7 1 38 10 294.2 4.9 2 1 25 275.7 5.1 2 3 30 226.1 5.3 1 32 20 82.8 3.9 1 38 11 85.8 2.5 2 1 26 156.1 4.9 2 3 31 133.5 7.2 1 32 21 63.3 4.7 1 38 12 73.1 4.1 2 1 27 146.5 4.6 2 3 32 169.3 6.6 1 32 22 40.6 10.9 1 38 13 123.6 3.0 2 1 28 83.0 6.9 2 3 33 73.8 13.5 1 33 6 164.6 4.5 1 38 14 139.7 2.8 2 1 29 153.8 4.8 2 4 0 276.1 5.8 I 33 7 100.9 2.1 1 38 15 94.1 3.8 2 1 30 113.2 11.0 2 4 1 363.5 11.2 1 33 8 150.0 2.3 1 39 8 191.5 5.9 2 1 31 103.6 8.7 2 4 2 320.8 7.9 1 33 9 40.7 4.4 1 39 9 205.5 7.2 2 1 32 305.7 6.0 2 4 3 206.9 1 33 10 250.1 3.9 1 39 10 192.3 3.3 2 1 33 147.1 5.6 2 4 4 820.4 21.8 1 33 11 222.6 3.5 1 39 11 109.1 2.3 2 1 34 74.3 14.7 2 4 5 212.0 4.1 1 33 12 255.9 4.0 1 39 12 115.8 2.7 2 2 2 259.0 5.5 2 4 6 46.2 3.2 1 33 13 158.1 3.1 1 39 13 130.4 2.7 2 2 3 163.9 3.9 2 4 7 123.5 2.4 1 33 14 157.6 9.1 1 39 14 220.0 5.5 2 2 4 471.2 9.8 2 4 8 368.7 5.4 1 33 15 324.6 4.9 1 40 8 17.8 7.0 2 2 5 287.7 5.9 2 4 9 276.8 1 33 16 216.7 3.5 1 40 9 172.3 3.8 2 2 6 103.2 2.2 2 4 10 317.6 1 33 17 212.8 3.6 1 40 10 127.2 2.3 2 2 7 317.4 4.6 2 4 11 83.3 3.6 1 33 18 96.1 4.5 1 40 11 110.5 2.8 2 2 8 317.1 4.5 2 4 12 336.6 1 33 19 149.2 4.1 1 40 12 123.6 3.8 2 2 9 383.7 5.8 2 4 13 300.2 1 33 20 189.2 3.5 1 41 9 61.8 4.8 2 2 10 201.0 3.3 2 4 14 256.1 3.9 1 33 21 16.7 8.1 2 0 3 343.8 15.4 2 2 11 327.9 4.7 2 4 15 308.4 4.8 1 34 7 54.5 2.7 2 0 4 229.6 6.6 2 2 12 175.8 3.1 2 4 16 147.7 4.3 1 34 8 213.0 3.4 2 0 5 154.2 5.2 2 2 13 469.1 6.3 2 4 17 98.7 1 34 9 174.9 2.8 2 0 6 319.3 7.6 2 2 14 492.6 6.7 2 4 18 630.4 1 34 10 183.4 2.8 2 0 7 362.2 8.8 2 2 15 232.7 3.8 2 4 19 1010.1 14.8 1 34 11 98.7 3.1 2 0 8 514.5 11.7 2 2 16 52.1 6.6 2 4 20 227.2 4.4 1 34 12 245.2 6.1 2 0 9 34.3 12.1 2 2 17 356.4 6.4 2 4 21 76.9 6.6 1 34 13 119g.0 3.2 2 0 10 366.1 8.0 2 2 18 440.3 6.4 2 4 22 163.8 4.4 SUBSTITUTE SHEET (RULE 28) WO 99/10379 PCT/GB98/02542 112- 2 4 23 132.1 4.2 2 6 28 86.7 12.0 2 8 32 255.5 4.9 2 11 5 355.1 4.7 2 4 24 58.8 10.6 2 6 29 208.2 13.3 2 8 33 128.2 6.5 2 11 6 284.5 5.1 2 4 25 59.4 12.6 2 6 30 85.3 9.3 2 9 0 404.2 7.9 2 11 7 351.7 5.3 2 4 26 189.2 4.4 2 6 31 307.5 5.8 2 9 1 531.7 9.7 2 11 8 240.9 3.4 2 4 27 26.4 11.3 2 6 32 218.8 7.1 2 9 2 249.8 3.0 2 11 9 147.7 3.1 2 4 28 120.4 5.3 2 6 33 196.9 5.3 2 9 3 302.2 4.2 2 11 10 180.9 3.2 2 4 29 133.1 7.3 2 7 0 610.6 18.5 2 9 4 77.5 2.3 2 11 11 443.5 6.3 2 4 30 202.9 6.0 2 7 1 428.4 6.7 2 9 5 277.2 4.7 2 11 12 282.2 4.2 2 4 31 162.8 7.8 2 7 2 652.5 14.8 2 9 6 222.5 3.9 2 11 13 843.9 12.3 2 4 32 176.8 5.8 2 7 3 291.0 4.6 2 9 7 141.0 3.1 2 11 14 280.8 2 4 33 173.4 5.8 2 7 4 185.1 2.9 2 9 8 339.3 4.7 2 11 15 388.1 5.7 2 5 0 307.4 5.1 2 7 5 217.1 3.0 2 9 9 537.1 8.1 2 11 16 55.7 13.7 2 5 1 553.9 9.1 2 7 6 470.1 6.2 2 9 10 177.6 2.8 2 11 17 414.0 5.8 2 5 2 95.0 2.1 2 7 7 285.1 4.0 2 9 11 627.2 9.3 2 11 18 33.4 13.3 2 5 3 320.1 7.9 2 7 8 566.6 8.2 2 9 12 237.6 3.7 2 11 19 544.4 7.8 2 5 4 603.9 9.8 2 7 9 348.9 4.7 2 9 13 598.9 8.9 2 11 20 116.4 4.9 2 5 5 153.0 2.7 2 7 10 155.1 2.8 2 9 14 144.8 3.0 2 11 21 28.7 11.6 2 5 6 570.3 9.7 2 7 11 441.1 6.6 2 9 15 314.7 5.5 2 11 22 272.3 2 5 7 325.8 4.4 2 7 12 569.2 8.3 2 9 16 327.8 5.3 2 11 23 258.6 4.1 2 5 8 457.8 6.2 2 7 13 366.5 5.1 2 9 17 252.2 4.5 2 11 24 160.4 4.8 2 5 9 187.1 3.1 2 7 14 647.6 9.3 2 9 18 327.8 5.1 2 11 25 191.8 4.6 2 5 10 321.5 5.7 2 7 15 462.3 6.6 2 9 19 185.1 4.0 2 11 26 194.9 4.8 2 5 11 189.7 3.0 2 7 16 84.3 13.3 2 9 20 348.8 5.5 2 11 27 106.6 8.2 2 5 12 279.4 4.4 2 7 17 332.2 6.0 2 9 21 148.3 4.7 2 11 28 247.3 18.6 2 5 13 80.5 5.0 2 7 18 457.3 7.4 2 9 22 146.8 5.4 2 11 29 52.8 13.9 2 5 14 181.0 4.0 2 7 19 254.3 4.4 2 9 23 291.4 4.7 2 11 30 210.8 2 5 15 832.8 12.1 2 7 20 265.0 4.5 2 9 24 90.2 5.8 2 11 31 119.1 2 5 16 560.4 9.6 2 7 21 34.2 13.6 2 9 25 243.1 4.8 2 11 32 113.3 5.9 2 5 17 361.8 5.4 2 7 22 95.8 6.2 2 9 26 265.5 4.9 2 12 0 99.2 2.4 2 5 18 136.5 5.2 2 7 23 71.7 9.3 2 9 27 112.7 6.1 2 12 1 109.9 1.6 2 5 19 314.5 5.0 2 7 24 447.0 5.7 2 9 28 99 .7 7.6 2 12 2 383.5 2 5 20 283.7 5.5 2 7 25 103.5 6.9 2 9 30 163 .0 6.0 2 12 3 520.6 7.3 2 5 21 216.1 4.9 2 7 26 21.0 9.8 2 9 31 393 .8 8.6 2 12 4 422.2 2 5 22 133.7 5.1 2 7 27 30.6 12.5 2 9 32 182.7 4.9 2 12 5 206.4 2.9 2 5 23 175.1 5.2 2 7 28 87.7 8.3 2 9 33 174.7 5.5 2 12 6 591.9 2 5 24 144.4 4.6 2 7 29 412.2 9.6 2 10 0 301.4 5.6 2 12 7 410.3 5.2 2 5 25 135.7 5.4 2 7 30 284.0 5.0 2 10 1 458.7 6.6 2 12 8 212.6 3.1 2 5 26 97.5 8.3 2 7 31 73.0 10.8 2 10 2 118.6 1.9 2 12 9 297.1 4.7 2 5 27 113.8 5.5 2 7 32 167.3 7.4 2 10 3 331.8 4.1 2 12 10 606.9 2 5 28 31.0 12.7 2 7 33 105.1 8.8 2 10 4 360.0 4.7 2 12 11 401.7 5.7 2 5 29 187.0 7.8 2 8 0 639.4 14.0 2 10 5 25.7 5.2 2 12 12 287.8 4.2 2 5 30 135.0 6.7 2 8 1 194.4 3.2 2 10 6 411.6 5.8 2 12 13 424.8 5.2 2 5 31 81.3 11.3 2 8 2 455.0 7.7 2 10 7 208.3 2.9 2 12 14 562.5 8.3 2 5 32 164.5 5.9 2 8 3 175.4 3.3 2 10 8 128.6 2.3 2 12 15 396.1 6.1 2 5 33 204.8 5.2 2 8 4 249.5 3.8 2 10 9 102.0 2.9 2 12 16 154.8 3.6 2 6 0 189.3 4.2 2 8 5 198.2 3.2 2 10 10219.6 3.4 2 1217 424.1 7.1 2 6 2 633.1 10.6 2 8 6 264.3 3.4 2 10 11 722.1 9.6 2 12 18 585.2 8.8 2 6 3 43.7 2.4 2 8 7 434.2 6.2 2 10 12 169.7 3.4 2 12 19 88.9 7.9 2 6 4 909.9 16.7 2 8 8 150.7 2.4 2 10 13 258.5 4.0 2 12 20 31.3 11.5 2 6 5 281.7 4.9 2 8 9 597.9 8.3 2 10 14 515.2 6.6 2 12 21 284.4 5.8 2 6 6 246.0 3.9 2 8 10 515.2 7.7 2 10 15 412.5 6.0 2 12 22 118.5 7.2 2 6 7 96.6 3.0 2 8 11 524.0 7.0 2 10 16 281.8 6.2 2 12 23 310.7 2 6 8 57.1 3.3 2 8 12 336.9 5.0 2 10 17 98.9 5.8 2 12 24 237.4 4.3 2 6 9 246.2 4.3 2 8 13 317.6 4.0 2 10 18 243.8 4.3 2 12 25 64.5 7.7 2 6 10 190.1 3.6 2 8 14 514.6 7.4 2 10 19 219.7 4.1 2 12 26 146.0 4.9 2 6 11 208.8 3.2 2 8 15 363.0 5.2 2 10 20 192.6 4.8 2 12 27 45.3 14.5 2 6 12 239.8 3.6 2 8 16 344.5 5.1 2 10 21 151.0 4.7 2 12 28 325.3 2 6 13 449.3 6.5 2 8 17 227.1 4.6 2 10 22 225.0 4.4 2 12 29 77.5 12.6 2 6 14 1047.3 14.3 2 8 18 234.0 4.2 2 10 23 146.8 4.6 2 12 30 106.4 7.2 2 6 I5 401.9 6.6 2 8 19 368.9 5.9 2 10 24 282.6 4.6 2 12 31 123.3 6.8 2 6 16 202.3 6.2 2 8 20 108.2 4.9 2 10 25 149.9 4.5 2 12 32 227.5 7.6 2 6 17 731.5 10.9 2 8 21 192.7 4.6 2 10 26 259.9 4.3 2 13 0 367.1 7.1 2 6 18 331.2 4.8 2 8 22 151.3 7.3 2 10 27 236.3 4.6 2 13 1 42.7 2.7 2 6 19 134.3 5.8 2 8 23 98.4 5.8 2 10 29 192.8 5.0 2 13 2 146.7 2.6 2 6 20 250.2 4.8 2 8 24 128.6 6.0 2 10 30 132.2 6.3 2 13 3 86.6 1.9 2 6 21 168.0 4.1 2 8 25 150.7 5.3 2 10 31 238.8 5.1 2 13 4 136.6 1.9 2 6 22 100.0 7.7 2 8 26 57.5 9.1 2 10 32 280.1 4.9 2 13 5 492.5 6.9 2 6 23 83.8 8.3 2 8 27 179.6 4.3 2 11 0 802.8 18.8 2 13 6 288.8 3.9 2 6 24 151.8 4.9 2 8 28 224.2 4.4 2 11 1 278.7 4.3 2 13 7 652.8 8.1 2 6 25 208.8 4.4 2 8 29 225.2 19.0 2 11 2 651.6 8.4 2 13 8 454.1 2 6 26 154.0 4.6 2 8 30 163.2 7.0 2 11 3 211.5 3.1 2 13 9 130.8 2 6 27 63.3 10.0 2 8 31 108.5 7.5 2 11 4 149.8 2.1 2 13 10 446.3 6.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -113- 2 13 11 303.1 4.3 2 15 18 232.4 4.1 2 17 28 57.0 15.5 2 20 8 537.8 2 13 12 765.0 10.8 2 15 19 63.7 7.2 2 17 29 255.6 4.7 2 20 9 378.0 5.3 2 13 13 435.7 6.8 2 15 20 361.1 5.6 2 17 30 26.8 12.3 2 20 10 127.5 2.9 2 13 14 139.7 3.8 2 15 21 318.0 5.0 2 17 31 200.4 4.5 2 20 11 294.2 4.2 2 13 15 405.4 6.8 2 15 22 113.8 4.4 2 18 0 767.9 21.3 2 20 12 173.9 2 13 16 158.5 4.8 2 15 23 305.8 5.7 2 18 1 107.5 2.5 2 20 13 189.7 4.7 2 13 17 178.1 3.9 2 15 24 109.7 4.8 2 18 2 555 .2 7.3 2 20 14 353.4 4.9 2 13 18 155.0 3.8 2 15 26 23.5 10.7 2 18 3 620 .2 8.0 2 20 15 467.2 7.8 2 13 19 166.4 4.2 2 15 27 349.9 8.4 2 18 4 516.0 6.9 2 20 16 443.6 6.9 2 13 20 93.0 10.3 2 15 28 333.7 6.8 2 18 5 529.1 7.4 2 20 17218.3 3.6 2 13 21 140.2 5.3 2 15 29 43.0 15.0 2 18 6 238.5 3.4 2 20 18 217.5 3.7 2 13 22 69.3 7.7 2 15 30 108.4 6.9 2 18 7 428.3 5.7 2 20 19 192.2 3.7 2 13 23 214.5 4.0 2 15 31 114.2 6.5 2 18 8 632.6 9.2 2 20 20 175.8 3.6 2 13 24 126.7 4.6 2 16 0 75.5 3.5 2 18 9 630.7 8.5 2 20 21 224.6 4.3 2 13 25 200.5 4.5 2 16 1 340.9 6.0 2 18 10 17.2 8.1 2 20 22 111.6 5.2 2 13 26 89.8 7.3 2 16 2 305.5 3.8 2 18 11 51.6 10.2 2 20 23 181.2 3.9 2 13 27 17.6- 8.9 2 16 3 247.7 3.3 2 18 12 429.7 6.3 2 20 24 91.0 6.3 2 13 29 159.7 7.2 2 16 4 195.5 2.4 2 18 13 371.0 5.2 2 20 25 326.7 10.9 2 13 30 131.4 5.9 2 16 5 388.3 5.2 2 18 14 485.6 7.3 2 20 26 104.4 2 13 31 193.3 4.8 2 16 6 25.9 8.0 2 18 15 328.3 4.8. 2 20 27 146.3 5.1 2 13 32 180.6 5.7 2 16 7 137.1 2.8 2 18 16 144.3 3.7 2 20 28 155.2 6.1 2 14 0 358.5 6.9 2 16 8 600.3 7.6 2 18 17 186.4 3.7 2 20 29 84.5 7.8 2 14 1 234.3 3.5 2 16 9 414.6 5.5 2 18 18 225.7 3.8 2 20 30 21.5 10.7 2 14 2 158.2 2.2 2 16 10 487.0 6.3 2 18 19 457.9 7.0 2 21 0 643.8 15.6 2 14 3 256.8 3.1 2 16 11 329.0 5.2 2 18 20 397.6 6.0 2 21 1 431.8 10.2 2 14 4 226.9 3.2 2 16 12 344.5 5.5 2 18 21 259.2 4.1 2 21 2 475.3 8.4 2 14 5 150.1 2.4 2 16 13 515.4 9.0 2 18 22 139.2 5.3 2 21 3 865.9 13.5 2 14 6 598.8 7.9 2 16 14 448.3 6.5 2 18 23 148.1 4.3 2 21 4 244.5 2 14 7 412.9 6.1 2 16 15 366.8 6.4 2 18 24 158.1 4.1 2 21 5 652.0 8.1 2 14 8 191.9 3.7 2 1616 245.4 4.0 2 18 25 57.3 11.0 2 21 6 222.5 3.9 2 14 9 767.1 10.5 2 16 17 73.2 5.4 2 18 26 216.7 9.1 2 21 7 102.4 4.2 2 1410 131.4 2.8 2 1618 196.2 4.1 2 18 27 95.3 7.0 2 21 8 310.7 4.7 2 14 11 530.5 7.3 2 16 19 134.6 4.5 2 18 28 141.2 4.4 2 21 9 59.3 5.9 2 14 12 399.3 5.8 2 16 20 70.5 7.8 2 18 29 136.3 5.6 2 21 10 206.0 3.7 2 14 13 277.4 4.4 2 16 21 155.5 4.5 2 18 30 64.2 9.5 2 21 11 321.0 4.4 2- 14 14 654.4- 7.9 2 16 22 221.9 4.0 2 19 1 413.1 7.0 2 21 12 460.1 6.6 2 14 15 202.0 3.7 2 16 23 260.2 4.5 2 19 2 355.4 4.7 2 21 13 235.7 3.9 2 14 16 137.0 5.0 2 16 24 141.5 7.3 2 19 3 277.9 3.5 2 21 14 377.4 5.8 2 14 17 160.2 5.0 2 16 25 265.2 5.3 2 19 4 435.2 5.8 2 21 15 213.9 4.1 2 14 18 236.0 3.9 2 16 26 75.7 8.2 2 19 5 613.0 7.8 2 21 16 246.8 4.1 2 14 19 152.2 5.2 2 16 28 154.3 5.4 2 19 6 301.5 4.3 2 21 17 357.7 5.1 2 14 20 137.4 3.8 2 16 29 190.8 4.8 2 19 7 248.0 4.0 2 21 18 118.6 2 14 21 33.5 13.3 2 16 30 103.0 7.4 2 19 8 329.7 5.3 2 21 19 52.5 7.8 2 14 22 69.7 7.8 2 16 31 145.0 9.4 2 19 9 774.7 9.2 2 21 20 83.7 5.6 2 14 23 50.6 10.5 2 17 0 548.7 15.7 2 19 10 748.5 10.2 2 21 21 135.6 3.6 2 14 24 154.6 6.6 2 17 1 137.7 2.4 2 19 11 695.7 8.6 2 21 22 191.5 4.4 2 14 25 159.6 5.5 2 17 2 500.7 6.2 2 19 12 472.3 7.0 2 21 23 259.5 4.3 2 14 26 110.9 6.4 2 17 3 742.2 9.7 2 19 13 337.5 5.8 2 21 24 21.1 10.6 2 14 27 245.4 6.2 2 17 4 589.3 7.7 2 19 14 374.3 5.7 2 21 25 123.7 5.3 2 14 28 160.8 5.5 2 17 5 714.7 9.6 2 19 15 203.0 3.8 2 21 26 85.3 7.1 2 14 29 220.0 4.4 2 17 6 1001.3 13.9 2 19 16 129.8 3.8 2 21 27 108.5 6.8 2 M4 30 229.6 5.3 2 17 7 432.3 5.6 2 19 17 212.5 3.8 2 21 28 184.9 4.4 2 14 31 50.6 16.2 2 17 8 99.9 2.7 2 19 18 217.1 3.8 2 21 29 123.3 6.6 2 14 32 210.4 5.0 2 17 9 220.6 3.4 2 19 19 295.6 4.5 2 22 0 301.9 8.2 2 15 0 308.1 6.1 2 17 10 335.1 4.9 2 19 20 283.8 4.2 2 22 1 377.9 10.2 2 15 1 264.4 3.9 2 17 11 611.8 7.8 2 19 21 245.9 4.2 2 22 2 508.8 14.1 2 15 2 502.5 6.7 2 17 12 131.5 3.9 2 19 22 108.7 4.2 2 22 3 122.3 2 15 3 178.6 2.4 2 17 13 259.0 4.0 2 19 23 47.7 10.4 2 22 4 443.6 5.7 2 15 4 534.6 7.2 2 17 14 534.8 9.2 2 19 24 91.9 6.3 2 22 5 591.8 8.2 2 15 5 365.0 4.9 2 17 15 212.4 4.2 2 19 25 16.6 8.4 2 22 6 30.0 8.9 2 15 6 414.3 5.8 2 17 16 184.5 4.4 2 19 26 25.4 11.6 2 22 7 184.2 2.7 2 15 7 524.2 6.9 2 17 17 304.0 4.2 2 19 27 108.6 5.1 2 22 8 82.9 2 15 8 507.0 7.6 2 17 18 103.1 4.1 2 19 28 68.0 11.0 2 22 9 259.4 2 15 9 180.3 2.6 2 17 19 165.6 4.2 2 19 29 61.9 9.2 2 22 10 188.3 2 15 10 201.0 3.3 2 17 20 256.8 4.3 2 19 30 155.5 6.9 2 22 11 460.7 5.9 2 15 11 434.1 6.3 2 17 21 130.7 4.3 2 20 0 757.7 20.1 2 22 12 14.3 7.1 2 15 12 226.7 4.7 2 17 22 113.6 5.1 2 20 2 92.1 2.3 2 2213 292.4 2 15 13 232.6 4.3 2 17 23 219.6 4.1 2 20 3 489.0 5.9 2 22 14 78.8 5.7 2 15 14 262.3 4.5 2 17 24 40.4 14.6 2 20 4 782.6 11.2 2 22 15 423.7 6.1 2 15 15 392.5 5.5 2 17 25 175.1 4.8 2 20 5 150.8 4.3 2 22 16 172.8 3.6 2 15 16 185.3 3.9 2 17 26 279.6 9.8 2 20 6 822.5 10.4 2 22 17210.2 3.7 2 15 17 387.7 5.4 2 17 27 171.6 4.8 2 20 7 562.6 7.2 2 22 18 173.3 4.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -114- 22 22 22 22 22 22 22 22 22 22 22 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 .23 23 23 23 23 23 24 24 24 24 24 24 24 24 24 24 24 24 2' 22' 2 2 Z 2' 2 2' 2 2 2 2~ 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 19 210.3 20 104.0 21 140.6 22 72.4 7 23 22.7 14 24 229.0 25 195.3 26 147.8 27 90.9 5 28 89.6 7 29 108.2 1 729.5 1 3 672.2 1 4 470.06 5 343.7 6 390.85 7 474.1 8 173.8 9 176.5 10 29.3 11 132.0 12 173.0 13 343.3 14 115.2 15 230.3 16 344.3 17 71.3 18 116.0 19 122.7 20 27.2 1 21 59.7 22 22.91 23 294.9 24 75.2 25 250.9 26 158.7 27 79.8 28 157.0 0 284.6 3 101.9 4 273.8 5 881.5 6 292.5 7 375.6 8 302.4 9 168.1 10 251.6 11 97.5 12 149.7 13 197.1 14 273.5 I15 91.4 I16 224.6 I17 127.0 118 354.3 1 19 244.8 4 20 120.5 4 21 122.8 4 22 108.6 4 23 204.0 4 24 91.3 4 25 136.7 4 26 100.6 4 27 177.6 4 28 132.9 5 4 19.3 5 5 204.3 5 6 252.6 5 7 166.5 5 8 280.1 ,5 9 314.6 10 261.4 3.6 4.0 4.5 '.2 0.2 7.1 4.2 4.5 .9 6.1 7.9 0.0 3.4 1.8 .6 1.2 8.6 3.2 3.1 5.1 3.8 3.3 5.6 5.9 3.5 4.5 .0.0 6.4 10.2 9.2 9.5 4.7 5.4 9.8 4.3 11.3 2.6 3.9 12.7 4.4 5.0 4.3 2.8 3.6 4.2 3.0 3.4 4.1 3.8 3.4 4.3 4.9 3.9 4.1 4.0 6.0 4.6 5.4 4.9 5.6 4.3 6.6 7.0 3.6 4.0 2.8 3.8 4.2 4.1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 26 2( 22 2 2' 2' 2' 2' 2' 2' 2 2 2' 12 Z2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 22 22 22 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 527 13 714 7 5 7 6 7 7 7 8 7 9 7 1I 7 1 7 1 7 1: 7 1.

7 1 7 1 7 1 7 1 7 1 7 2 .7 2 :7 2 :7 2 :7 2 ~7 2 ~7 2 18 28 28 28 Z8 28 315.8 7 80.4 3.

94.6 3.

118.6 3 469.7 6 363.6 5 282.9 4 158.4 2 198.8 3 286.0 4 141.7 3 174.5 1 148.9 4 88.8 6 160.8z 170.7 217.0 40.0 3.

67.1 3.

238.1 3 310.7 4 331.1 5 402.2 5 183.9 131.8 240.5 243.7 201.2 81.05 142.3 13.0 94.8 .296.5.

I52.9 308.1 182.9 53.5 I78.8 132.7 170.5 128.0 1 339.3 1 240.4 463.4 165.1 139.6 82.4 P82.0 0 48.4 1 132.7 2 150.6 3 151.1 4 245.3 5 256.2 6 223.1 7 218.7 8 261.2 9 98.1 0 220.0 1 108.7 .2 144.5 :3 106.9 :4 93.6 ~5 223.7 ~6 152.8 4 130.3 5 133.4 6 90.7 7 268.8 8 215.1 9 439.2 10 223.4 .1 9 .0 8 .6 .4 .3 '.5 3.6 .5 7.4 1.2 .9 1.1 1.3 4.5 9 1 .2 .3 .2 '.5 3.3 3.1 3.6 4.0 3.2 3.4 3.7 5.6 t. 1 4.2 7.9 13.6 3.7 6.2 5.9 5.6 .3.1 .2.4 4.6 5.5 2.3 2.5 Z.8 3.0 4.8 2.7 3.1 2.8 3.8 3.9 3.5 4.0 4.9 4.6 14.5 4.5 3.9 5.4 5.7 4.3 4.2 3.2 2.3 2.1 3.8 3.0 5.9 3.3 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 28 2 29J 2 29J 2 2S 2 2 2 2 2 2 2 2~ 2 2' 2 2' 2 2' 2 2' 2 2' 2 2' 2 2' 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 2 3 2 3 2 3 2 3 2 3 223 223 223 223 223 223 223 223 2: 2: 2: 2: 2: 2: 2: 2.

2 2 2 2 2 2 2 2 2 2 2 2 2 2 9 9 9 9 9 9 9 9 9 9 9 9 9 9 0 34 3' 3' 3 3 3 3 3 3 3 3 3 2 3 3 11 229.9 3 12 209.3 2) 13 201.8 3 14 232.3 3 15 247.04 16 211.1 3 17 100.83 18 159.23 19 109.6 2, 20 151.83 21 97.1 4 22 73.4 8 23 222.5 24 47.9 1' 25 232.6 4 236.5 8 5 298.2 8 6 305.9 4 7 326.6 41 8 113.2 2 9 312.9 4 10 253.4 11 54.8 4 12 211.7 13 348.0 14 81.84 15 106.6 16 280.3 17 230.9 18 241.9 19 53.44 20 160.2 21 162.9 22 72.2 23 120.8 24 68.3 I5 262.4 46 259.7 I7 75.2 4 I8 214.9 49 113.1 10 55.9 11 189.9 12 75.7 13 173.0 )14 239.9 15 97.2 0 16 37.3 0 17 135.4 0 19 168.2 0 20 163.6 0 21 105.9 0 22 243.7 0 23 70.0 0 24 89.4 1 4 126.4 1 5 118.8 1 6 241.6 1 7 235.1 1 8 160.5 1 9 218.6 1 10 213.6 1 11 305.2 1 12 179.2 1 13 203.2 1l 14 131.6 31 15 121.8 31 16 230.5 31 17 204.8 31 18 219.7 31 19 31.2 31 20 69.4 .7 .4 .3 .4 3.5 3.5 3.2 1.4 3.8 .4 .5 3.9 4.5 4.2 .7 .6 '.7 .2 .3 3.5 1 3.1 5.1 1.4 3.0 4.8 3.5 5.5 6.2 3.8 3.4 6.1 5.5 6.0 5.2 3.6 3.2 3.1 2.2 3.8 2.8 3.4 2.8 3.6 3.4 8.3 10.3 4.3 4.6 4.1 4.0 5.8 6.3 3.6 2.2 3.3 3.3 2.6 3.5 3.0 4.5 3.0 3.0 3.3 4.1 9.5 3.7 4.4 10.8 5.0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 31 21 31 22 31 23 32 5 32 6 327 32 8 32 9 32 IC 32 11 32 12 32 13 32 14 32 11 32 16 32 12 32 11 32 1' 32 24 32 2' 32 2: 33 6 33 7 33 8 33 9; 33 1 33 1 33 1 33 1 33 1 33 1 33 1 *33 1 *33 1 33 1 33 2 33 2 34 34 34 234 234 1 1 34 1 2 34 2 341 2 34 2 34 2 34 2 34 2 34 2 34 2 34 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 35 2 36 2 36 2 36 2 36 2 36 2 36 2 36 52.3 8.

115 .0 3 31.8 11 417.6 9.

177.3 2.

245.9 3 87.7 2.

234.3 3 180.9 2 220.2 2 30.3 7 255.1 4 114.4 3 381.0 6 139.0 2 266.62 249.5 132.4 160.4 79.8 6 52.3 7 236.7 6 317.2 4 105.7 2 72.7 2 108.6 1182.0 2397.0 3252.5 t 17.6 1 5 45.75 6 14.8 7 63.2 8 38.6 1 9 142.5 0 68.7 1 145.3 70.9 2 83.6 2 3314.2 73.4 2 0 59.7 1 104.3 2 176.3 3 222.7 4 210.5 5 100.1 6 152.2 7 173.6 8 84.7 9 88.2 10 20.2 7 51.3 8 198.8 9 139.3 10 166.4 11 16.1 12 361.4 13 64.1 14 152.1 15 192.4 16 62.7 17 75.0 18 41.5 19 182.6 7 210.1 8 19.8 9 47.3 10 39.5 11 162.6 12 124.1 13 65.4 6 7 .9 .6 .8 .8 4 .9 2 .3 3.6 3.8 3.8 t.3 3.4 3.4 .6 '.7 .9 .4 .7 2.2 2.9 7.1 7.6 3.2 3.6 1.3 1.4 0.2 3.3 5.4 3.7 .8 .4 4.4 3.3 4.3 6.6 3.2 3.3 3.8 3.1 4.4 4.4 8.9 3.8 3.4 4.7 7.7 7.1 4.1 3.3 3.7 4.7 8.9 3.9 10.2 8.2 3.7 4.4 2.7 SUBSTITUTE SHEET (RULE 26) WO 99/1 0379 -115- 2 36 14 66.0 4.1 2 36 15 114.8 3.2 2 36 16 41.4 7.7 2 36 17 66.2 4.8 2 36 18 222.2 3.8 2 37 7 25.3 6.8 2 37 8 174.1 4.6 2 37 9 115.8 2.4 2 37 10 129.3 2.3 2 37 11 69.1 3.0 2 37 12 155.7 2.8 2 37 13 108.7 3.3 2 37 14 54.0 5.7 2 37 15 100.8 3.4 2 37 16 12.8 6.3 2 38 8 181.2 5.0 2 38 9 77.7 3.2 2 38 10 198.5 3.2 2 38 11 52.7 3.9 2 38 12 98.8 2.5 2 38 13 37.2 6.7 2 38 14 69.4 3.8 2 38 15 158.4 3.4 2 39 8 113.0 2.8 2 39 9 218.4 3.7 2 39 10 64.3 3.2 2 39 11 108.3 2.8 2 39 12 97.3 2.6 2 39 13 130.0 3.1 2 40 9 53.0 3.2 2 40 10 85.4 2.8 2 40 11 47.3 4.0 2 41 9 86.1 5.7 3 0 0 723.5 23.0 3 0 1 6.8 4.9 3 0 3 492.1 10.4 3 0 5 555.2 12.5 3 0 6 512.0 10.5 3 0 7 112.1 4.0 3 0 8 64.7 5.0 3 0 9 229.2 4.9 3 0 10 56.0 5.7 3 0 11 446.0 8.5 3 0 12 141.2 4.6 3, 0 13 478.7 9.1 3 0 14 537.8 12.2 3 0 15 138.0 5.2 3 0 16 42.9 19.9 3 0 17 139.4 6.4 3 0 18 92.5 11.4 3 0 19 100.1 7.6 3 0O 20 67.7 12.1 3 0 21 349.1 7.1 3 0 22 145.8 7.6 3 0 23 14.7 11.0 3 0 24 195.5 6.0 3 0 25 302.5 8.6 3 0 26 15.5 11.5 3 0 27 117.1 9.8 3 0 28 88.6 11.3 3 0 29 181.3 13.6 3 0 30 127.6 12.8 3 0 31 137.6 10.0 3 0 32 383.2 9.3 3 0 33 57.3 23.9 3 1 0 278.3 6.4 3 1 1 141.5 2.6 3 1 2 212.2 3.7 3 1 3 434.6 5.9 3 1 4 279.5 5.1 3 1 5 544.7 8.6 3 1 6 148.2 2.7 1 7 230.8 3.9 1 8 238.9 3.5 1 9 257.0 4.2 1 10 74.7 3.2 1 11 375.2 7.1 1 12 598.4 8.6 1 13 760.7 10.3 1 14 499.9 7.4 1 15 232.9 3.8 1 16 246.3 5.2 1 17 508.1 7.9 1 18 126.1 5.2 1 19 599.1 8.8 1 20 409.6 6.0 1 21 189.3 4.4 1 22 121.6 6.0 1 23 297.5 5.0 1 24 130.7 4.9 1 25 187.5 4.8 1 26 184.2 5.0 1 27 67.3 13.0 1 28 245.2 5.9 1 29 327.4 15.6 1 30 154.7 7.0 1 31 148.2 '8-8 1 32 78.2 11.2 1 33 25.8 12.4 2 0 387.0 9.5 2 1 603.3 10.5 2 2 326.9 5.3 2 4 171.7 3.0 2 5 180.5 3.3 2 6 378.7 5.6 2 7 249.4 3.8 2 8 473.3 7.3 2 9 153.5 3.4 2 10 116.5 3.2 2 11 372.3 5.1 2 12 91.3 3.6 2 13 421.6 5.6 2 14 361.0 5.3 2 15 255.2 4.0 2 16 448.5 6.7 2 17 421.8 6.4 2 18 652.5 8.6 2 19 45.9 13.7 2 20 216.2 4.4 2 21 168.6 4.5 2 22 143.4 5.2 2 23 113.1 6.2 2 24 148.9 4.4 2 25 263.4 5.2 2 26 194.2 5.0 2 27 138.4 6.4 2 28 65.8 14.3 2 29 329.9 15.1 2 30 42.9 16.0 2 31 68.0 14.8 2 32 190.9 5.4 2 33 101.9 13.8 3 0 339.3 6.1 3 1 593.9 10.5 3 2 465.1 8.6 3 3 539.5 10.1 3 4 321.6 5.0 3 5 365.9 6.4 3 6 130.1 2.4 3 7 216.3 3.2 3 8 518.9 7.8 3 9 149.1 3.0 3 10 390.0 5.9 3 11 375.4 7.0 3 12 563.8 7.7 3 13 380.6 5.4 3 14 361.0 5.0 3 15 147.7 3.3 3 16 315.7 6.9 3 17 343.9 5.2 3 18 241.7 4.2 3 19 287.6 5.2 3 20 174.0 4.8 3 21 161.9 5.3 3 22 225.4 4.9 3 23 203.3 4.3 3 24 32.0 13.0 3 25 193.5 4.7 3 26 49.5 16.0 3 27 118.4 7.3 3 28 130.0 6.3 3 29 330.2 13.3 3 30 187.0 6.2 3 31 422.0 6.9 3 32 53.4 15.5 3 33 38.4 15.8 4 0 386.0 9.2 4 1 571.3 9.3 4 2 412.0 6.8 4 3 432.1 7.9 4 4 243.6 3.6 4 5 320.7 5.4 4 6 468.4 7.0 4 7 414.2 6.1 4 8 221.2 3.4 4 9 467.5 5.9 4 10 541.4 7.3 4 11 439.4 6.8 4 12 367.3 5.0 4 13 419.5 5.5 4 14 288.9 4.1 4 15 418.6 6.0 4 16 428.9 6.6 4 17 227.9 7.5 4 18 243.9 4.2 4 19 171.2 4.2 4 20 96.1 7.0 4 21 270.4 4.6 4 22 117.7 6.8 4 23 308.8 5.3 4 24 168.0 4.5 4 25 108.1 6.9 4 26 129.7 6.5 4 27 104.3 7.2 4 28 81.5 10.1 4 29 470.7 12.4 4 30 233.6 5.3 4 31 136.4 7.8 4 32 93.7 10.9 4 33 181.0 6.2 5 0 201.9 3.5 5 1 653.5 11.9 5 2 534.9 10.4 5 3 482.6 8.1 5 4 314.6 5.3 5 5 29.2 7.8 5 6 317.3 4.5 5 7 257.1 3.5 5 8 197.6 3.1 5 9 52.9 6.2 5 10 358.2 5.0 5 11 393.0 6.2 5 12 246.6 3.7 5 13 436.8 5.9 5 14 492.0 7.3 5 15 416.9 6.0 PCT/GB98/02542 3 5 16 351-.6 3 5 17 663.2 9.6 3 5 18 235.2 4.2 3 5 19 323.3 3 5 20 535.3 7.3 3 5 21 16.3 8.2 3 5 22 104.6 3 5 23 131.4 4.3 3 5 24 98.9 5.8 3 5 25 56.5 10.3 3 5 26 84.4 8.3 3 5 27 108.6 7.8 3 5 28 209.8 5. 3 3 5 29 367.2 10 .6 3 5 30 63.3 17.0 3 5 31 152.8 5.9 3 5 32 156.7 6.7 3 5 33 114.5 8.4 3 6 0 639.9 15.9 3 6 1 658.8 15.2 3 6- 2 223.5 3.3 3 6 3 420.6 5.7 3 6 4 237.1 3.7 3 6 5 491.4 7.9 3 6 6 575.3 8.3 3 6 7 192.3 3 6 8 234.2 3.6 3 6 9 408.2 5.3 3 6 10 155.2 3.2 3 6 11 209.5 3.3 3 6 12 425.0 6.4 3 6 13 320.2 3 6 14 770.3 11.2 3 6 15 16.3 8.2 3 6 16 93.8 4.9 3 6 17 474.4 3 6 18 545.0 8.2 3 6 19 153.9 4.2 3 6 20 216.4 4.3 3 6 21 249.9 3 6 22 108.8 5.6 3 6 23 78.4 7.2 3 6 24 213.5 4.8 3 6 25 192.3 4.7 3 6 26 73.6 7.9 3 6 27 198.8 4.7 3 6 28 70.4 3 6 29 204.2 17.8 3 6 30 51.4 15.5 3 6 31 138.0 7.2 3 6 32 211.3 3 6 33 118.3 9.3 3 7 0 667.7 15.1 3 7' 1 439.5 6.4 3 7 2 225.8 3.3 3 7 3 315.2 4.6 3 7 4 471.8 3 7 5 22.7 7.3 3 7 6 182.4 2.7 3 7 7 148.2 3.1 3 7 8 470.5 6.7 3 7 9 229.2 3.3 3 7 10 535.3 3 7 11 275.5 3.8 3 7 12 282.4 3 7 13 1023.3 13.9 3 7 14 838.3 11.5 3 7 15 165.7 3 7 16 325.9 3 7 17 530.2 7.8 3 7 18 249.0 3 7 19 513.8 8.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -116- 251.1 4.3 21 91.6 8.5 22 28.8 12.5 23 160.8 4.7 24 160.8 4.1 195.2 5.0 26 260.0 4.9 27 173.9 4.7 28 20.8 10.1 29 28.6 14.5 282.7 5.3 31 128.3 7.2 32 25.6 12.4 33 186.0 7.1 0 752.3 16.8- 1 680.2 12.5 2 90.2 2.2 3 216.2 3.7 4 253.3 3.3 107.5 2.8 6 141.8 2.8 7 169.5 2.7 8 217.2 3.1 9 258.9 3.6 574.6 7.8 11 732.4 9.2 12 372.5 5.5 13 876.6 11.6 14 431.8 6.7 323.6 5.4 16 144.2 8.4 17 626.7 8.7 18 394.0 6.0 19 228.6 5.0 182.3 4.0 21 234.7 4.2 22 93.0 8.7 23 241.4 4.1 24 83.5 8.1 74.6 9.2 26 19.8 9.7 27 123.6 6.1 28 20.0 10.0 29 41.3 16.0 115.8 8.0 31 120.6 8.4 32 175.1 6.0 33 183.8 7.0 0 197.1 3.3 1 275.9 4.1 2 890.9 13.0 3 374.5 4.7 4 40.3 3.6 421.8 6.5 6 270.2 3.8 7 183.5 2.7 8 480.4 7.1 9 191.8 3.5 561.5 7.9 11 144.0 3.1 12 577.9 7.8 13 603.4 8.9 14 166.8 4.5 189.4 3.8 16 388.2 7.0 17 581.6 8.5 18 70.1 7.7 19 273.3 5.2 39.4 12.7 21 352.1 5.7 22 185.4 4.0 23 260.3 4.3 9 24 9 25 9 26 9 28 9 29 9 30 9 31 9 32 9 33 10 0 10 1 10 2 10 3 10 4 10 5 10 6 10 7 10 8 10 9 10 10 10 11 10 12 10 13 10 14 10 15 10 17 10 18 10 19 10 20 10 21 10 22 10 23 10 24 10 25 10 26 10 27 10 28 10 29 10 3Y 10 31 10 3: 11 0 11 1 11 2 11 3 11 4 11 5 11 6 11 7 11 8 11 9 11 2i 11 1 11 2: II 1 11 1 11 1 11 2 11 2 204.0 332.7 242.8 29.6 1: 264.8 110.4 236.0 93.3 8 55.4 1 449.0 375.9 262.7 400.8 319.0 227.9 180.5 75.2 3 230.8 189.1 138.1 574.8 478.9 401.9 553.3 562.1 165.4 62.1 128.2 201.7 458.3 142.8 75.6 164.5 161.4 93.5 151.3 338.4 89.6 80.9 I97.8 197.6 434.9 282.1 385.5 186.3 133.2 153.2 125.8 318.1 790.8 850.7 0 704.9 1 401.1 2 568.7 3 329.4 4 368.8 5 268.9 6 47.8 7 137.9 8 142.1 9 298.0 0 203.0 1 157.9 2 257.1 3 395.2 4 170.1 5 157.3 6 101.4 7 61.7 .8 200.7 9 119.4 0 133.5 4.4 5.0 4.4 5.0 5.0 7.3 5.6 .2 7.4 8.8 5.1 3.3 5.7 4.1 3.3 2.6

I

3.3 2.8 2.9 9.0 6.3 5.6 7.1 7.6 4.7 8.2 4.8 4.1 6.4 3.6 6.8 5.7 4.5 5.9 5.7 11.9 11.2 11.1 11.0 5.0 6.6 3.8 6.7 2.7 2.2 2.8 2.3 4.1 10.0 12.1 10.6 5.7 7.5 4.6 5.8 4.8 9.6 5.2 3.4 4.7 3.9 5.9 4.2 7.0 4.1 5.0 6.9 11.9 12.5 6.6 5.8 3 1 82.2 8.5 32 240.8 5.9 0 306.9 5.2 1 207.3 3.5 2 169.6 2.5 3 326.5 4.2 4 238.6 3.3 5 509.7 7.3 6 485.7 6.3 7 967.5 16.0 8 548.5 8.2 9 467.6 6.6 10 633.5 9.4 11 214.4 3.2 12 123.0 3.1 13 378.6 5.3 14 267.3 4.1 15 537.8 6.9 16 207.4 3.9 17 334.8 5.6 18 399.5 7.3 19 267.1 4.6 20 129.1 5.2 21 115.5 5.2 22 175.5 3.7 23 177.8 3.8 24 282.4 5.1 25 271.9 4.4 26 146.3 5.8 27 31.0 12.8 29 127.0 5.4 30 51.9 14.8 31 109.0 7.0 32 188.1 5.6 0 93.3 2.6 1 184.2 2.8 2 168.0 2.4 3 356.0 4.7 4 389.7 5.2 5 102.8 2.6 6 1150.5 18.9 7 299.1 4.2 8 238.1 3.2 9 641.6 8.3 10 254.1 3.6 11 351.5 4.8 12 520.2 7.1 13 301.1 5.4 14 194.1 8.0 15 428.5 6.0 16 194.2 3.8 17 297.5 4.3 18 197.3 3.8 19 157.4 4.6 20 172.1 4.0 21 32.9 12.6 22 148.3 4.2 23 145.5 4.0 24 163.9 3.9 25 139.0 5.2 26 89.9 7.7 28 277.2 5.2 29 120.0 6.6 30 249.1 5.4 32 49.4 17.1 0 205.9 3.8 11 319.5 4.9 12 364.6 4.8 1 3 335.3 4.3 1 4 552.4 7.6 1 5 628.3 8.5 16 335.6 4.5 394.9 5.7 530.5 7.4 673.1 8.9 303.7 588.0 7.7 334.9 5.7 326.0 4.7 25.1 10.4 277.3 4.4 186.2 3.6 258.5 4.4 136.1 3.6 171.9 3.9 178.4 3.9 259.8 294.2 287.7 328.8 5.2 198.2 4.4 151.4- 4.3 373.7 9.9 77.1 8.2 254.6 4.8 136.1 8.1 104.1 10.8 25.0 5.9 530.4 9.7 686.2 8.8 238.4 3.3 985.6 17.5 466.0 6.4 328.3 4.2 340.1 4.9 160.8 3.7 604.1 9.3 342.9 176.9 232.6 3.9 252.2 4.6 152.9 3.3 100.5 383.6 5.9 147.1 4.4 223.1 3.9 165.7 4.2 174.1 3.9 279.2 131.4 3.7 254.1 4.4 1113.8 212.6 5.1 274.2 1136.4 5.8 44.4 15.6 206.1 4.8 1 144.4 5.9 308.7 6.1 311.9 5.2 453.5 139.8 2.6 506.7 6.7 144.1 239.2 4.1 133.7 330.9 4.4 422.2 D 536.0 7.6 1 281.0 3.9 2 327.3 5.4 3 306.0 4.6 4 198.2 3.8 5 169.1 3.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCTIGB98/02542 -117- 16 251.8 4.1 17 88.4 6.1 18 425.8 5.7 19 275.8 4.3 231.4 4.1 21 147.8 4.7 22 193.9 4. 3 23 372.4 6.0 24 221.9 4.0 62.2 11.4 26 259.4 6.0 27 217.3 4.9 28 36.6 15.7 29 179.3 5.1 67.7 13.1 31 170.5 5.6 0 393.6 8.1 1 322.7 6.0 2 128.3 2.0 3 200.4 2.9 4 604.0 8.4 583.8 8.3 6 275.0 3.9 7 797.2 10.4 8 176.2 2.7 9 461.4 7.1 180.7 3.1 11 247.7 7.1 12 454.1 6.4 13 222.0- 4.1 14 413.9 5.6 242.0 3.9 16 221.9 4.0 17 171.0 3.6 18 107.5 4.4 19 95.1 4.9 96.6 5.0 21 157.7 4.3 22 173.2 4.1 23 172.5 4.2 24 225.6 4.2 107.0 5.6 26 357.4 13.0 27 80.0 9.1 28 142.5 5.0 29 172.7 5.1 208.0 5.7 0 449.8 8.2 1 405.1 8.6 2 533.4 6.5 3 448.8 5.5 4 698.5 8.8 676.8 8.8 6 1169.4 13.7 7 180.1 2.9 8 356.2 6.1 9 885.6 11.9 586.2 8.7 11 85.8 5.3 12 158.7 3.3 13 545.8 7.7 14 306.9 4.6 525.7 8.3 16 144.3 3.5 17 448.4 7.8 18 129.4 3.8 119 318.0 5.0 120 196.9 3.9 21 72.8 6.5 22 290.0 4.6 t23 134.1 4.3 1 24 108.5 6.2 106.3 5.9 62.5 10.3 79.2 11.0 217.5 4.4 122.3 5.8 64.1 10.5 365.2 6.6 315.0 5.3 290.8 4.6 554.4 7.6 1010.1 12.9 168.6 2.6 437.3 9.1 265.3 3.9 316.7 4.2 458.7 7.7 149.6 2.9 159.8 3.1 197.9 3.6 266.8 5.1 247.5 4.1 75.1 5.1 251.7 4.1 241.4 3.9 117.1 4.1 88.4 6.0 379.3 5.5 137.7 4.1 277.1 4.5 186.8 3.8 34.9 12.7 451.2 14.4 44.7 13.6 47.6 13.3 205.0 5.2 136.2 .5.9 I184.6 5.4 510.8 10.8 228.4 4.1 430.0 6.5 651.9 8.1 225.5 4.4 114.8 3.7 189.2 3.6 136.0 5.0 770.1 9.9 197.5 3.3 454.6 6.3 1214.1 3.5 428.1 7.3 5286.6 4.1 t 254.0 4.0 5112.5 4.1 5222.4 3.8 7 258.0 4.0 3142.1 3.6 289.0 4.5 255.6 4.2 1 154.7 4.0 2 106.9 6.0 3 250.3 5.1 4 16.7 8.4 6 128.4 7.4 7 123.0 8.0 8 116.5 7.0 9 95.9 8.3 )606.2 17.7 1176.5 3.6 1401.7 5.9 5324.9 4.2 t 407.1 5.8 5 582.5 8.0 6 629.0 9.4 7 479.9 5.9 8 345.4 4.7 9 86.1 4.0 10 178.6 3.3 11 208.8 3.4 12 215.2 4,1 13 277.4 5.9 14 285.4 4.2 15 118.3 3.4 16 191.2 3.6 17 172.9 3.6 18 182.2 3.3 19 45.8 10.5 20 136.5 4.0 21 309.5 5.1 22 106.9 4.9 23 24.2 11.1 24 274.0 11.6 25 103.2 6.7 26 132.7 4.7 27 93.6 8.4 28 191.0 5.0 29 109.2 7.8 0 488.7 8.6 1 517.9 9.4 2 198.4 4-.9 3 294.1 3.8 4 436.4 5.6 5 54.8 3.7 6 516.4 7.0 7 461.7 7.2 8 444.9 6.7 9 197.2 3.7 10 149.6 3.3 11 283.2 4.5 12 282.2 4.9 13 413.4 6.0 14 262.7 3.8 15 71.2 4.5 16 286.4 4.2 17 293.2 4.9 18 87.7 5.0 19 145.3 3.5 20 112.8 3.9 21 249.5 3.9 22 23.0 10.8 23 188.1 4.4 24 31.2 12.7 25 68.3 9.2 26 123.0 5.7- 27 26.9 11.8 28 31.2 13.5 0 150.3 3.2 1 110.3 2.8 2 373.1 6.6 3 391.3 4.8 4 433.5 5.5 15 285.4 3.9 1 6 416.3 5.4 1 7 344.0 4.5 58 305.9 4.0 59 161.5 3.0 10 102.9 3.3 11 281.9 4.3 312 264.2 5.7 3 13 105.0 4.9 3 14 138.1 3.3 3 15 199.4 3.4 3 16 144.1 3.7 3 17 60.2 7.1 3 18 101.9 4.5 23 1 23 2 23 2 123 2 23 2 23 2 123 2 123 2 1 23 2 23 2 124 524 124 1 24 524 524 1 24 524 24 1 5 24 24 1 524 1 3 24 1 3 24 1 3 24 1 3 24 1 3 24 1 3 24 1 3 24 1 3 24 1 3 24 3 24 3 24 3 24 3 24 3 24 3 24 3 24 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 25 3 26 3 26 3 26 3 26 3 26 3 26 3 26 124.9 24.7 10.4 217.8 150.4 5.1 109.2 17.4 161.2 202.5 4.3 100.0 7.3 130.5 6.1 65.4 9.7 108.7 2.6 137.8 2.9 306.5 307.2 4.8 320.1 4.2 408.5 5.4 337.9 360.3 5.3 302.8 3.9 140.3 3.2 338.0 102.3 4.1 201.7 3.8 211.8 157.1 4.3 46.7 9.2 174.4 17.4 8.7 38.7 9.1 126.0 3.9 260.7 233.1 269.2 11.2 51.7 9.8 128.6 5.1 153.7 159.1 4.3 145.8 4.9 543.5 11.6 187.6 432.6 7.7 483.1 707.9 8.7 685.5 9.3 386.0 244.9 3.6 235.9 3.3 55.0 5.2 1 15 1.1 2.7 194.2 391.6 5.1 1296.3 4.6 1353.3 5.2 i82.6 4.1 i24.8 9.7 7113.6 5265.2 4.3 )154.3 3.8 130.7 4.1 Z 76.1 7.4 3 88.5 6.8 4 59.1 8.2 5 62.5 9.3 5 129.2 5.2 7 193.5 4.8 1206.9 6.3 386.4 10.1 315.2 5.6 183.7 2.4 1 199.8 2.6 5189.0 ;55.8 3.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -118- 326 7 394.4 4.9 3 29 5 102.1 2.1 3 32 16 297.0 4.7 3 37 12 72.3 3 26 8 252.4 3.5 3 29 6 36.2 4.7 3 32 17 130.1 3.5 3 37 13 107.8 3.2 3 26 9 171.0 3.0 3 29 7 130.9 2.9 3 32 18 153.6 4.6 3 37 14 36.2 7.9 3 26 10 76.7 4.6 3 29 8 209.2 3.1 3 32 19 125.6 3.9 3 37 15210.7 326 11 79.7 3.7 3 29 9 237.6 3.7 3 32 20 173.8 3.6 3 37 16 191.9 6.3 3 26 12 207.8 3.3 3 29 10 136.3 3.0 3 32 21 158.2 4.6 3 38 7 163.6 4.4 3 26 13 136.5 3.3 3 29 11 53.1 5.0 3 32 22 93.4 6.7 3 38 8 72.1 2.8 3 26 14 153.5 3.0 3 29 12 254.5 3.7 3 33 5 87.1 4.1 3 38 9 204.6 3.4 3 26 15 283.3 4.0 3 29 13 326.2 4.6 3 33 6 140.4 2.3 3 38 10 102.2 2.7 3 26 16 169.4 3.4 3 29 14 66.9 6.2 3 33 7 176.4 2.8 3 38 11 117.8 3.3 3 26 17 291.1 4.8 3 29 15 41.4 9.2 3 33 8 47.7 4.9 3 38 12 180.1 3 26 18 37.5 10.4 3 29 16 128.5 3.1 3 33 9 96.2 2.8 3 38 13 113.2 2.9 3 26 19 220.3 3.8 3 29 17 206.3 3.4 3 33 10 229.6 3.3 3 38 14 179.1 3.7 3 26 20 307.3 5.0 3 29 18 306.4 16.5 3 33 11 175.2 2.9 3 38 15 46.6 9.6 3 26 21 26.3 12.3 3 29 19 50.5 9.4 3 33 12 103.3 4.0 3 39 8 319.8 6.7 3 26 22 46.4 12.5 3 29 20 172.5 4.5 3 33 13 221.3 8.2 3 39 9 98.7 2.6 326 23 163.3 4.1 3 29 21 142.2 4.5 3 33 14 116.4 4.6 3 39 10 140.2 3 26 24 93.9 9.9 3 29 22 50.1 10.6 3 33 15 87.5 3.9 3 39 11 64.8 4.4 3 26 25 166.2 4.6 3 29 23 319.6 5.3 3 33 16 187.7 3.6 3 39 12 88.0 3 26 26 175.5 5.1 3 29 24 193.4 3.9 3 33 17 171.3 3.4 3 39 13 108.9 5.6 3 27 2 361.9 9.8 3 30 3 401.7 9.5 3 33 18 137.6 4.3 3 40 7 218.6 7.6 3 27 3 149.7 4.1 3 30 4 323.9 6.1. 3 33 19 182.4 3.5 3 40 8 85.1 3 27 4 284.3 3.8 3 30 5 161.1 2.4 3 33 20 120.0 5.2 3 40 9 104.6 3 27 5 294.4 4.2 3 30 6 24.4 7.2 3 33 21 118.1 4.3 3 40 10 24.2 3 27 6 225.8 3.0 3 30 7 269.9 4.1 3 34 5 183.8 3.5 3 40 11 130.7 4.3 3 27 7 36.1 6.8 3 30 8 91.1 2.5 3 34 6 115.5 2.1 3 41 8 162.3 4.7 3 27 8 78.5 3.1 3 30 9 155.4 2.7 3 34 7 158.4 2.4 4 0 0 334.0 8.2 3 27 9 293.3 4.1 3 30 10 69.7 3.5 3 34 8 72.6 3.1 4 0 1 534.8 18.4 3 27 10 163.1 2.7 3 30 11 209.8 3.2 3 34 9 234.1 3.6 4 0 2 252.0 3 27 11 309.7 5.4 3 30 12 155.8 2.9 3 34 10 129.2 3.3 4 0 3 201.1 3 27 12 168.6 2.8 3 30 13 35.9 9.4 3 34 11 280.0 7.4 4 0 4 253.3 5.6 3 27 13 143.1 2.8 3 30 14 72.8 4.5 3 34 12 106.7 3.6 4 0 5 779.2 14.7 3 27 14 229.9 3.8 3 30 15 40.0 8.1 3 34 13 211.4 3.8 4 0 6 285.4 6.2 3 27 15 125.4 3.3 3 30 16 129.5 4.0 3 34 14 207.8 4.5 4 0 7 188.2 4.2 327 16 145.4 3.5 3 30 17 318.2 8.4 3 34 15 141.8 3.3 4 0 8 874.7 16.9 3 27 17 146.0 3.6 3 30 18 217.0 4.0 3 34 16 14.0 7.0 4 0 9 83.4 4.8 3 27 18 89.0 4.8 3 30 19 88.6 6.1 3 34 17 20.0 9.1 4 0 10 393.0 3 27 19 23.1 10.4 3 3020 101.7 5.1 3 3418 218.1 3.6 4 0O1l 9.7 7.2 3 27 20 201.9 12.5 3 30 21 64.8 6.7 3 34 19 66.8 5.3 4 0 12 796.3 17.4 3 27 21 219.4 5.3 3 30 22 101.8 6.8 3 34 20 34.1 12.0 4 0 13 521.5 10.2 3 27 22 29.0 11.8 3 30 23 36.7 11.5 3 35 6 80.2 4.0 4 0 14 636.6 11.6 3 2723 171.2 5.0 3 31 3 310.0 7.7 3 35 7 74.1 3.3 4 0 15 167.2 5.6 3 27 24 154.2 4.8 3 31 4 102.1 4.0 3 35 8 259.6 5.7 4 0 16 207.7 3 27 25 180.9 4.6 3 31 5 128.8 2.8 3 35 9 282.1 8.2 4 0 17 276.6 16.9 3 27 26 94.5 6.9 3 31 6 153.3 2.4 3 35 11 103.3 3.0 4 0 18 273.7 7.4 3 28 2 189.5 4.4 3 31 7 202.3 3.0 3 35 12 162.6 2.9 4 0 19 22.6 15.1 3 28 3 80.5 2.7 3 31 8 59.7 3.5 3 35 13 20.0 9.1 4 0 20 212.3 6.1 3 28 4 218.2 3.2 3 31 9 141.0 2.4 3 35 14 127.2 3.0 4 0 22 '283.0 6.8 3 28 5 399.9 5.5 3 31 10 85.4 2.9 3 35 15 108.5 3.9 4 0 23 82.4 8.7 3 28 6 187.9 2.6 3 31 11 52.0 4.9 3 35 16 26.6 10.1 4 0 24 17.0 11.7 3 28 7 63.7 3.2 3 31 12 169.7 3.0 3 35 17 92.0 3.6 4 0 25 15.6 11.3 3 28 8 298.4 4.1 3 31 13 88.8 3.5 3 35 18 86.6 5.3 4 0 26 112.2 9.8 3 28 9 107.5 3.2 3 31 14 112.2 3.5 3 35 19 38.8 14.9 4 0 27 38.6 23.8 3 28 10 115.2 2.5 3 31 15 126.5 4.6 3 36 0 8.4 2.0 4 0 28 200.3 9.6 3 28 11 150.2 2.9 3 31 16 154.2 14.8 3 36 6 170.2 4.7 4 0 29 250.8 26.6 3 28 12 135.8 3.1 3 31 17 155.6 3.7 3 36 7 207.9 4.7 4 0 30 225.3 8.2 3 28 13 64.4 4.9 3 31 18 169.6 3.5 3 36 8 132.5 2.6 4 0 31 85.4 21.0 3 28 14 32.8 9.2 3 31 19 50.4 7.1 3 36 9 152.5 2.4 4 0 32 19.7 14.5 3 28 15 117.7 3.5 3 31 20 141.9 4.7 3 36 10 216.8 3.2 4 0 33 98.5 15.7 3 28 16 17.8 8.8 3 31 21 43.2 13.1 3 36 11 20.2 8.5 4 1 0 722.2 14.2 3 28 17 76.7 4.9 3 31 22 177.6 3.6 3 36 12 197.2 3.4 4 1 1 464.6 7.8 3 28 18 165.0 4.1 3 31 23 99.8 9.2 3 36 13 175.0 3.9 4 1 2 535.3 8.9 3 28 19 316.0 10.5 3 32 5 221.0 4.2 3 36 14 144.4 3.0 4 1 3 394.7 5.6 3 28 20 106.6 4.7 3 32 6 97.9 2.1 3 36 15 180.5 3.5 4 1 4 347.2 5.2 3 28 21 101.5 5.2 3 32 7 146.6 2.3 3 36 16 154.8 3.6 4 1 5 435.5 6.7 3 28 22 81.9 7.3 3 32 8 90.4 2.8 3 36 17 65.6 8.1 4 1 6 275.6 4.4 3 28 23 205.0 4.1 3 32 9 107.4 2.6 3 37 6 118.0 4.3 4 1 7 171.4 2.9 3 28 24 148.4 4.5 3 32 10 123.2 3.2 3 37 7 176.8 5.6 4 1 8 475.8 6.6 3 28 25 37.7 13.6 3 32 11 111.5 4.5 3 37 8 130.9 2.6 4 1 9 155.3 3.3 3 29 2 543.7 12.9 3 32 12 37.9 8.3 3 37 9 143.4 2.7 4 1 10 .120.5 2.9 3 29 3 124.5 3.9 3 32 13 84.8 4.1 3 37 10 97.1 2.7 4 1 11 628.2 8.3 3 29 4 258.0 4.9 3 32 14 314.9 8.4 3 37 11 80.2 3.2 4 1 12 442.3 6.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02 542 -119- 417.8 5.8 382.8 6.0 357.8 4.7 223.8 4.5 294.9 6.1 453.0 7.5 311.7 4.5 87.7 7.9 105.7 7.6 268.4 4.6 97.0 4.9 157.1 3.8 257.2 4.4 208.3 4.7 116.3 6.9 153.8 5.5 220.6 16.9 192.7 5.8 95.4 12.9 217.1 7.2 58.3 16.8 316.9 4.6 432.8 7.7 503.3 7.7 500.9 9.0 457.8 6.0 521.5 7.6 185.2 2.9 143.0 2.6 194.9 3.1 545.6 7.7.

680.5 9.1 390.9 5.5 504.8 7.1 878.9 11.9 775.4 12.3 324.5 4.6 230.4 3.9 779.1 10.7 262.5 4.6 224.9 4.4 249.9 6.5 211.8 4.0 144.1 4.6 50.3 10.0 114.8 5.4 133.3 5.1 288.3 5.2 126.0 6.4 1160.4 5.6 P37.2 18.1 124.9 7.7 153.0 8.4 28.8 13.6 1181.8 6.5 69.3 2.1 140.7 3.0 364.2 5.0 444.9 7.2 50.7 4.3 173.2 2.9 357.0 5.5 318.6 5.1 45.9 5.5 452.5 6.1 325.2 4.3 1 184.1 3.0 2 321.3 4.4 3 426.9 5.7 4 518.7 7.3 419.3 6.0 6 185.2 3.8 82.7 8.9 94.1 7.0 433.4 6.5 147.1 4.6 348.4 5.2 150.1 4.2 270.1 4.7 102.6 6.0 325.5 5.2 107.3 7.6 130.0 7.3 122.5 7.4 164.6 6.3 494.1 7.2 201.5 6.2 148.8 7.4 671.1 14.1 255.7 4.2 648.5 10.2 239.5 3.5 274.7 3.9 537.8 7.8 146.9 3.1 463.0 7.3 121.1 3.0 20.3 7.7 205.1 3.0 400.7 5.3 597.1 8.3 433.0 5.5 26.6. 10.6 488.3 7.2 370.5 5.4 395.4 5.4 275.8 5.8 229.6 4.3 116.3 5.1 397.1 6.3 196.4 3.9 21.6 10.0 151.0 4.2 96.1 6.6 196.1 4.7 132.5 5.7 166.3 6.2 158.0 6.0 87.9 10.5 t37.7 15.2 272.6 4.3 725.1 10.1 85.2 2.8 220.7 3.6 230.2 3.5 84.1 2.6 43.4 4.5 532.8 7.5 182.3 2.9 101.7 3.1 )455.2 6.3 1 102.3 3.5 2 316.7 4.8 3 512.3 6.6 4 580.6 8.0 5 150.8 13.7 6 195.2 4.6 7 304.1 4.3 8 206.9 4.8 9 69.5 9.3 0 310.5 5.2 1 477.0 6.9 2 222.3 3.9 3 318.8 5.0 216.0 4.4 110.8 6.8 20.2 9.8 95.4 8.9 107.6 8.3 192.4 7.9 39.4 15.5 55.6 15.6 127.6 11.7 166.9 2.6 371.1 5.9 495.0 8.3 430.7 5.7 64.0 2.6 495.3 6.5 173.0 2.8 154.5 2.6 477.7 6.6 625.2 8.7 362.1 5.3 490.4 7.0 282.8 4.5 364.0 5.3 898.7 11.9 208.2 5.9 227.2 11.2 233.8 4.3 346.4 6.1 309.5 4.7 306.3 4.8 159.2 5.2 196.3 4.0 114.2 4.7 17.4 8.5 298.4 4.4 218.8 5.2 160.7 4.7 34.7 14.0 250.9 6.1 99.7 8.7 264.5 5.2 134.1 7.4 84.9 11.0 691.4 12.0 298.9 4.2 519.0 7.4 256.7 3.7 285.0 3.8 233.1 4.3 163.9 2.9 307.0 4.3 174.2 3.0 332.3 5.1 345.2 4.9 1 400.9 5.2 !603.1 8.2 3 430.5 5.8 1 407.7 5.6 5 316.8 4.6 5 239.1 7.0 7 200.0 4.1 8 243.3 5.2 9 123.4 5.3 0 319.5 5.2 1 147.5 3.7 2 274.8 4.7 3 181.9 3.8 4 168.1 3.8 5 95.6 6.3 6 239.9 4.5 7 164.8 6.0 8 86.3 20.0 7 29 7 30 7 31 7 32 8 0 8 1 8 2 8 3 8 4 8 5 8 6 8 7 8 8 8 9 8 10 8 11 8 12 8 13 8 14 8 15 8 16 8 17 8 18 8 19 8 20 8 21 8 22 8 23 8 24 8 25 8 26 8 27 8 28 8 29 8 30 8 31 8 3: 9 0 9 1 9 2 9 3 9 4 9 5 9 6 9 7 9 8 9 9 9 1i 9 1 9 1: 9 1~ 9 1.

9 1 9 1 9 1 9 1 9 1 9 2 9 2 9 2 9 2 9 2 9 2 9 2 9 2 9 2 19 2 19 3 1 93 19 3 t 10 1 10 191.5 107.4 135.6 68.7 1 203.9 3 510.0 348.1 331.0 116.3 441.6 497.9 265.1 223.4 267.9 408.4 938.2 708.6 751.2 318.3 709.0 560.7 375.8 189.3 205.2 72.1 256.3 338.4 321.3 58.4 263.0 198.3 264.1 366.5 P89.4 1 121.4 25.4 64.6 27 1.1 321.5 308.5 97.9 533.2 201.8 336.1 175.3 155.6 272.6 0 194.0 1 77.8 2 929.3 3 725.4 4 211.0 5 195.5 6 454.9 7 78.4 8 342.7 9 170.4 0 338.3 1 197.5 2 113.5 3 204.5 4 257.2 .5 76.0 .6 228.5 :7 105.2 8 350.4 ~9 202.2 0 147.4 11 32.4 12 169.3 0 397.8 1 41.6 4.9 8.4 7.9 7.6 1.7

I

1.8 S.3 5.6 5.3 5.7 3.3 3.7 6.2 13.0 10.1 11.0 4.8 9.7 7.9 6.3 5.3 9.3 4.4 4.8 5.1 8.1 4.6 4.8 17.0 [0.9 7.2 12.7 15.5 4.3 4.6 2.3 7.6 2.9 4.7 2.7 2.8 3.8 3.1 11.8 10.7 5.6 5.6 5.2 3.9 5.7 3.9 5.1 3.8 4.4 7.4 4.2 10.2 5.6 6.8 14.5 8.3 5.8 3.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -120- 161.8 -2.4 446.3 6.4 191.9 2.8 219.5 3.4 287.1 4.2 126.2 2.3 486.6 6.3 355.1 4.4 193.9 3.0 239.1 3.6 803.5 12.3 315.4 4.4 358.5 5.0 429.9 6.7 421.1 6.1 333.6 6.5 256.9 4.1 69.3 7.9 126.8 4.4 204.1 3.9 199.9 4.5 254.1 4.2 42.5 12.0 72.3 9.3 250.9 4.6 208.3 4.5 118.1 9.0 153.2 7.2 1307.3 5.4 118.5 7.7 168.6 6.4 128.8 2.6 276.8 5.0 654.4 9.0 404.8 5.5 97.8 2.2 159.2 2.6 378.4 4.7 516.1 6.9 319.4 4.7 598.3 9.6 692.6 11.6 1 395.5 5.3 ?264.8 4.4 3 114.9 6.8 1 303.0 5.1 446.7 6.3 202.8 4.7 7 161.4 6.4 9 367.8 5.5 S273.4 4.9 D 147.9 4.0 1 432.7 6.4 2 150.5 4.1 3 172.6 4.0 4 385.8 5.5 185.0 5.0 6 307.0 4.7 7 165.2 4.9 8 23.2 10.9 9 170.0 5.5 0 108.3 7.2 1 137.3 5.8 2 37.1 14.4 161.5 3.6 1 313.2 5.1 2 339.6 4.3 3 227.3 3.5 4 520.8 6.2 164.3 2.7 6 306.8 4.5 7 420.7 6.3 8 649.9 9.6 9 727.0 9.8 10 717.8 10.4 11 417.9 6.3 12 369.3 6.3 13 60.2 8.7 14 196.8 6.4 15 503.2 7.4 16 14.8 7.5 17 92.8 6.7 18 195.1 4.0 19 410.7 6.0 20 211.1 4.3 21 260.1. 4.3 22 107.8 4.7 23 162.9 4.0 24 224.6 3.9 25 121.8 6.2 26 185.4 4.6 27 59.2 22.4 28 152.9 5.2 29 74.4 9.5 30 102.3 8.2 31 70.0 10.9 32 65.1 14.3 0 361.3 6.8 1 429.2 6.3 2 386.4 4.7 3 163.9 2.6 4 495.3 6.8 5 241.6 3.2 6 309.9 4.5 7 809.8 11.0 8 189.4 3.0 9 124.2 2.9 10 649.2 8.3 11 299.5 4.4 12 524.0 6.9 13 224.0 4.6 14 430.0 6.0 15 211.6 3.8 16 91.3 5.3 17 260.3 4.5 18 98.3 6.1 19 213.6 4.1 20 125.5 4.2 21 171.3 4.0 22 101.1 6.2 23 199.9 4.6 24 132.4 6.4 25 20.6 9.8 26 28.0 12.8 27 207.6 14.2 28 245.4 5.0 29 108.1 7.3 30 64.2 12.9 131 129.2 7.8 10 37.0 3.8 1 489.0 8.6 1 2 138.8 2.6 1 3 178.8 2.7 14 491.7 8.1 t5 807.4 10.5 t 6 752.6 10.5 t 7 127.4 2.6 1 8 512.4 6.6 4 9 347.1 5.5 4 10 703.7 10.2 4 11 413.1 6.6 4 12 327.9 5.2 4 13 101.8 7.2 4 14 234.6 3.9 155.0 3.6 208.9 3.7 525.8 7.6 200.2 4.4 171.8 4.4 130.4 4.6 16.4 8.0 110.9 4.9 182.9 3.9 25.6 10.9 225.4 4.2 27.7 12.8 116.1 7.8 31.2 13.9 40.9 14.3 167.0 5.5 23.0 11.2 193.7 4.8 96.3 3.1 1191.8 33.4 738.7 9.5 652.4 7.6 183.4 2.9 380.6 5.1 347.7 4.9 389.9 5.3 136.9 2.9 41.5 17.3 362.8 5.4 865.8 11.8 507.9 7.5 208.6 4.1 433.8 5.9 72.2 6.1 220.7 3.5 145.9 3.9 I44.0 10.7 1287.7 4.4 186.4 3.9 t222.4 4.0 ;209.3 3.9 1115.7 4.7 ;217.2 4.3 i70.8 21.3 1 80.5 10.8 3263.3 5.0 )171.4 5.9 26.3 12.2 1 117.2 7.9 1446.3 7.1 256.4 4.4 544.1 7.6 302.8 4.0 426.5 5.8 377.5 5.7 431.8 5.2 82.5 4.2 1 82.4 3.2 )326.5 5.9 0 222.7 3.6 1 276.6 6.1 2 141.9 3.6 3 285.9 4.5 4 368.6 5.6 5 217.6 3.9 6 471.0 6.2 7 218.4 3.8 8 177.6 3.7 9 269.6 4.1 0 58.9 7.7 A 212.5 3.7 2 356.4 5.1 23 56.9 11.5 24 200.1 5.2 25 68.3 8.1 26 247.1 12.7 27 200.5 4.8 28 156.3 5.3 29 84.0 11.5 30 209.0 6.7 0 812.7 16.4 1 270.7 5.4 2 128.3 3 280.2 4 890.8 12.1 5 710.4 10.1 6 906.6 11.6 7 503.0 7.3 8 305.7 5.1 9 104.5 10 226.8 8.8 11 333.9 5.2 12 204.4 3.7 13 396.2 5.7 14 568.8 10.4 15 121.0 3.7 16 396.0 6.6 17 131.5 4.2 18 200.5 3.6 19 26.5 10.5 20 335.1 6.4 21 141.1 3.8 22 189.8 3.7 23 107.1 4.7 24 42.5 13.6 25 191.9 5.1 26 178.5 6.2 27 78.0 28 135.7 5.8 29 80.7 9.2 30 111.1 7.8 0 186.5 3.8 1 466.4 8.2 2 400.2 6.9 3 405.1 5.8 4 328.6 4.2 5 94.0 2.6 6 536.8 7.3 7 194.0 47.1' 8 101.7 2.9 9 622.5 9.2 10 295.9 11 606.0 8.8 12 231.8 13 210.4 3.6 14 182.9 15 195.7 16 265.6 17 162.1 3.8 18 57.6 19 240.5 20 226.4 121 60.7 7.8 ;22 219.8 4.7 123 163.3 124 206.8 4.2 125 262.4 26 189.5 5.9 27 254.4 6.9 328 63.6 11.6 329 134.0 6.6 3 30 83.5 9.3 0 334.1 5.6 1 429.4 7.3 SUBSTITUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -121- 261.7 3.7 241.8 3.4 563.1 8.2 405.0 5.7 347.9 6.1 190.8 3.7 335.5 5.9 198.2 3.2 238.3 3.8 400.6 5.9 490.7 6.4 187.3 3.5 30.9 10.2 98.6 4.3 230.5 3.6 235.1 3.9 143.2 3.8 196.2 3.9 417.7 6.0 41.9 14.5 96.8 5.4 77.7 6.7 62.0 15.2 28.9 13.2 77.5 7.3 139.1 5.6 52.2 15.8 131.6 6.1 583.8 11.1 265.4 5.6 320.7 5.9 401.5 5.5 488.6 6.8 544.7 7.4 320.1 5.1 466.9 5.7 29.5 8.4- 276.3 4.8 I394.0- 5.7 581.6 8.7 237.8 3.7 483.4 7.0 1 145.6 3.8 i172.9 3.2 i41.1 9.2 1 224.2 4.3 3185.2 3.6 )216.3 3.7 79.4 5.5 1 39.7 11.2 2 157.5 4.5 3 251.7 5.0 4 387.1 12.0 175.4 5.7 198.8 4.9 7 134.9 5.3 8 96.9 6.8 9 92.5 11.8 I460.4 9.0 352.8 8.2 380.2 7.2 1257.7 4.3 I 323.6 5.8 5811.8 11.8 S295.3 4.3 7 366.8 4.6 3134.5 2.9 282.2 4.2 0 181.4 3.6 1 245.7 3.6 2 262.9 3.8 3 278.2 4.0 337.3 5.0 122.8 3.2 63.2 5.9 105.9 4.2 134.4 3.4 89.3 5.7 165.6 4.1 253.0 4.1 183.7 4.1 143.5 5.2 21.6 10.2 224.6 4.4 105.0 7.6 156.2 6.7 149.6 5.8 190.2 3.9 52.5 5.5 227.2 4.3 488.0 6.3 119.5 2.4 749.7 9.5 300.2 4.6 90.7 3.8 135.7 2.7 218.9 3.5 84.5 3.4 227.1 3.5 83.6 4.3 91.6 4.9 40.7 7.9 102.4 3.3 128.1 4.2 194.6 3.3 305.2 4.4 206.0 3.7 76.6 5.6 80.1 6.4 187.4 4.3 418.1 19.4 170.3 4.7 196.5 4.5 48.7 12.8 92.2 8.5 33.4 14.1 100.4 3.8 129.1 5.4 383.7 6.2 561.3 9.6 470.5 6.6 371.3 5.4 287.4 4.0 137.8 2.5 236.1 3.4 28.4 9.6 14.4 6.8 1 47.6 6.6 Z 219.2 3.4 3 132.4 3.4 4 170.3 3.3 5 251.0 3.7 5 253.0 3.9 7 110.9 3.4 8 184.0 3.4 9 67.5 6.0 0 58.1 9.0 1 121.9 4.9 2 339.8 7.4 3 85.3 6.5 4 130.6 5.6 5 249.4 4.8 6 73.2 8.6 7 72.3 10.2 0 95.7 3.6 1 103.0 2.8 2 203.8 4.2 3 203.6 3.1 4 556.8 7.6 5 502.8 6.7 6 321.9 4.5 7 314.5 4.0 8 144.9 2.7 9 381.6 6.2 10 137.1 3.2 11 211.1 3.4 12 244.2 3.8 13 261.4 4.7 14 42.6 9.7 15 104.9 3.4 16 168.5 3.2 17 148.8 3.3 18 202.5 3.4 19 171.2 4.3 20 72.1 5.4 21 125.0 4.9 22 135.9 5.9 23 139.6 5.0 24 154.5 5.1 25 107.5 5.5 26 67.9 12.2 27 24.8 11.5 0 162.7 3.0 1 274.8 5.1 2 387.5 6.4 3 209.8 3.3 4 548.3 7.0 5 565.0 7.7 6 391.3 5.6 7 162.9 3.4 8 170.9 3.1 9 216.5 3.3 10 65.4 4.0 11 81.7 3.4 12 282.6 4.9 13 76.8 4.3 14 210.1 3.5 15 128.5 3.5 16 285.5 4.6 17 295.1 5.7 18 205.9 3.6 19 177.3 3.5 20 254.0 4.9 21 653.5 23.0 22 68.4 7.4 23 47.3 13.0 24 127.1 6.2 25 102.3 7.2 26 30.2 11.9 0 334.8 5.7 1 553.0 10.8 2 185.9 3.6 3 59.6 3.8 4 266.2 4.3 5 106.9 2.4 6 235.9 3.2 7 157.9 3.0 8 104.0 2.9 9 57.9 5.0 10 391.2 5.3 11 198.8 3.2 12 103.4 3.8 13 272.5 4.2 14 83.6 4.6 15 232.8 3.5 16 28:5.1 4.2 84.0 4.7 52.6 7.6 223.0 3.9 321.2 11.6 103.3 5.6 138.3 4.6 88.5 7.1 108.7 5.3 105.5 95.1 10.0 267.6 4.8 81.2 5.4 303.5 5.8 201.1 3.7 358.4 33.4 7.1 130.6 2.3 201.6 3.2 201.7 3.1 381.2 5.4 15.8 7.4 130.9 3.4 44.6 6.1 141.2 3.2 221.0 3.8.

142.6 3.3 160.8 3.3 137.7 3.8 185.6 3.6 196.5 10.3 105.8 141.3 3.9 115.0 5.1 164.7 4.3 236.4 4.6 186.0 314.1 5.6 313.5 294.1 5.3 83.9 3.2 192.2 3.1 243.8 3.3 182.1 2.6 220.6 199.5 3.2 19.1 7.7 49.3 5.6 180.5 3.3 127.1 2.8 198.0 3.4 t 64.5 4.7 512.6 6.4 5 105.8 3.9 7 260.9 5.1 3 184.9 )96.3 8.2 )125.8 4.3 1 150.6 4.1 2 32.4 11.5 3 133.3 5.3 4 156.4 5.1 56.5 3.2 238.3 4.6 274.4 4.9 242.1 4.6 144.7 2.8 i295.1 3.9 i300.6 4.3 1 205.4 3.1 114.5 49.8 5.4 0 214.8 3.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -122- 4 29 11 45.1 6.7 4 32 11 112.1 3.0 4 36 13 58.4 6.8 5 1 5 110.7 4 29 12 96.7 3.1 4 32 12 137.7 3.0 4 36 14 24.6 10.2 5 1 6 313.7 4.2 4 29 13 249.0 3.6 4 32 13 38.1 13.4 4 36 15 238.6 4.1 5 1 7 317.7 4.4 4 29 14 15.8 7.7 4 32 14 246.2 8.4 4 36 16 31.3 10.7 5 1 8 235.3 4 29 15 16.4 8.0 4 32 15 35.3 11.6 4 36 17 26.2 10.7 5 1 9 435.8 5.6 4 29 16 64.9 5.7 4 32 16 17.6 8.7 4 37 4 312.5 14.9 5 1 10 141.7 2.9 4 29 17 209.9 6.9 4 32 17 133.0 3.9 4 37 6 311.2 5.3 5 I 11 333.2 4 29 18 59.2 11.5 4 32 18 150.7 4.9 4 37 7 96.1 2.7 5 1 12 227.9 3.7 4 29 19 214.7 4.9 4 32 19 34.6 13.5 4 37 8 74.9 3.3 5 1 13 349.0 5.3 4 29 20 72.7 6.3 4 32 20 18.6 8.8 4 37 9 90.5 3.2 5 1 14 445.9 6.3 4 29 21 140.8 5.1 4 32 21 36.3 11.4 4 37 10 29.6 9.2 5 I I5 465.6 7.2 4 29 22 27.7 12.6 4 33 1 257.1 7.6 4 37 11 59 .4 5.2 5 1 16 595.9 8.9 4 29 23 242.6 4.7 4 33 2 157.4 4.1 4 37 12 98.2 3.5 5 I 17 310.1 4.4 4 29 24 184.0 4.7 4 33 3 128.4 4.0 4 37 13 185.7 4.1 5 1 18 493.0 7.1 4 30 0 297.8 4.8 4 33 4 87.1 3.0 4 37 14 104.3 3.7 5 I 19 280.0 4 30 1 187.0 4.9 4 33 5 231.3 4.3 4 37 15 144.9 3.4 5 1 20 82.7 6.! 4 30 2 88.5 2.7 4 33 6 246.2 3.6 4 38 6 77.8 2.8 5 1 21 131.7 7.1 4 30 3 91.6 3.1 4 33 7 267.4 4.1 4 38 7 163.9 2.6 5 1 22 150.9 5.1 4 30 4 109.5 2.4 4 33 8 103.9 2.7 4 38 8 148.9 2.5 5 1 23 208.0 3.9 4 30 5 262.9 3.6 4 33 9 18.8 7.9 4 38 9 236.7 3.7 5 1 24 61.9 11.3 4 30 6 231.4 3.0 4 33 10 72.3 3.7 4 38 10 206.1 3.3 5 1 25 94.0 7.7 4 30 7181.0 2.9 4 3 311 117.0 3.2 4 3811 122.4 3.1 5 1 26 106.4 6.4.

4 30 8 164.4 2.6 4 33 12 220.6 6.8 4 38 12 162.5 3.0 5 1 27 141.6 5.1 4 30 9 147.3 2.6 4 33 14 96.8 4.7 4 38 13 117.3 3.5 5 1 29 319.9 5.4 4 30 10 120.1 2.9 4 33 15 110.2 3.7 4 38 14 52.6 7.9 5 1 30 60.7 16.9 4 30 11 169.5 3.3 4 33 16 88.7 5.7 4 39 6 90.2 2.8 5 1 31 162.3 9.8 4 30 12 82.2 3.9 4 33 17 160.3 4.2 4 39 7 211.6 4.5 5 1 32 100.6 12.8 4 30 13 196.0 3.2 4 33 18 156.2 3.8 4 39 8 159.6 3.3 5 2 0 300.9 4.1 4 30 14 151.3 3.4 4 33 19 149.7 3.9 4 39 9 81.0 3.4 5 2 1 94.3 4 30 15 151.6 3.4 4 33 20 64.8 8.0 4 39 10 163.9 3.0 5 2 2 235.1 3.6 4 30 16 219.8 16.0 4 34 1 263.2 7.2 4 39 11 104.7 2.9 5 2 3 217.5 3.2 4 30 17 210.8 3.8 4 34 4 144.9 3.9 4 39 12 133.1 3.3 5 2 4 344.6 5.8 4 30 18 94.4 5.8 4 34 5 115.6 4.3 4 40 6 162.2 7.5 5 2 5 640.2 8.4 4 30 19 121.1 5.1 4 34 6 25.4 8.0 4 40 8 182.2 3.2 5 2 6 256.8 3.7 4 30 20 148.9 4.3 4 34 7 118.7 3.2 4 40 10 49.9 6.4 5 2 7 844.6 11.4 4 30 21 66.7 6.8 4 34 8 164.2 3.4 4 41 7 122.4 4.5 5 2 8 298.9 4.1 4 30 22 72.4 9.7 4 34 924.6 9.6 5 0 049.1 3.8 5 29 403.8 5.9 4 30 23 184.9 5.9 4 34 10261.0 11.4 5 0 1 246.7 5.5 5 2 10 317.0 4.9 4 31 0 23.4 8.6 4 34 11 108.0 5.0 5 0 2 174.9 4.2 5 2 11 500.5 6.8 4 31 1 61.1 2.6 4 34 12 88.2 3.8 5 0 3 44.3 7.9 5 2 12 388.9 5.6 4 31 2 165.1 3.6 4 34 13 145.2 3.2 5 0 4 69.1 5.6 5 2 13 606.5 8.4 4 31 3 217.7 4.1 4 34 14 163.0 3.5 5 0 5 280.6 5.8 5 2 14 259.4 4 31 4 222.8 4.4 4 34 15 124.0 4.2 5 0 6 1070.6 28.4 5 2 15 443.2 6.3 4 31 5 196.1 3.3 4 34 16 129.9 4.0 5 0 7 150.1 3.8 5 2 16 482.4 7.3 4 31 6 220.5 3.7 4 34 17 102.8 4.7 .5 0 8 732.5 15.4 5 2 17 527.0 7.3 4 31 7 160.7 2.7 4 34 18 30.0 11.3 5 0 9 353.4 7.1 5 2 18 406.6 6.2 4 31 8 76.6 2.8 4 34 19 97.1 4.5 5 0 10 82.7 5.1 5 2 19 85.2 6.2 4 31 9 107.4 3.0 4 35 0 128.0 3.9 5 0 11 14.4 10.0 5 2 20 322.5 5.2 4 31 10 253.1 3.8 4 35 4 103.6 4.6 5 0 12 15.5 11.2 5 2 21 214.0 5.9 4 31 11 203.6 2.9 4 35 5 71.5 3.8 5 0 13 19.8 12.7 5 2 22 155.4 4 31 12 91.6 3.2 4 35 6 253.7 5.0 5 0 14 578.0 11.4 5 2 23 304.8 4.7 4 3.1 13 175.1 3.9 4 35 7 94.6 9.5 5 0 15 481.4 10.1 5 2 24 62.2 10.0 4 31 14 23.7 10.2 4 35 8 186.0 7.4 5 0 16 265.8 19.6 5 2 25 213.3 4.2 4 31 15 261.6 8.4 4 35 9 215.3 4.5 5 0 17 240.5 5.9 5 2 26 73.8 12.0 4 31 16 51.1 9.6 4 35 10 165.0 3.5 5 0 18 263.0 6.8 5 2 27 165.8 4 31 17 70.3 5.8 4 35 11 199.2 3.9 5 0 19 16.3 11.7 5 2 28 76.9 19.8 4 31 18 85.2 6.1 4 3512 167.0 3.4 5 0 20 21.9 13.8 5 2 29 71.8 16.4 4 31 19 66.2 9.2 4 35 13 223.7 3.8 5 0 21 176.2 5.4 5 2 30 109.4 9.3 4 31 20 49.2 13.1 4 35 14 150.0 3.5 5 0 22 63.6 13.9 5 2 31 177.1 4 31 21 13.7 6.9 4 35 15 33.2 11.3 5 0 23 152.1 5.9 5 2 32 269.8 4 31 22 16.2 8.1 4 35 16 42.5 13.0 5 0 24 89.9 17.5 5 3 0 769.8 17.4 4 32 0 131.8 3.6 4 35 17 72.5 6.6 5 0 25 12.9 9.5 5 3 1 196.4 3.2 4 32 1 87.2 3.6 4 35 18 116.0 6.2 5 0 26 129.1 7.0 5 3 2 307.2 6.1 4 32 2 191.6 5.6 4 36 4 251.5 8.3 5 0 27 68.5 14.0 5 3 3 139.2 4 32 3 242.1 6.0 4 36 5 137.7 10.6 5 0 30 56.1 28.9 5 3 4 218.7 4 32 4 142.9 3.2 4 36 6 216.3 4.3 5 0 31 29.4 20.1 5 3 5 144.7 4 32 5 172.4 3.1 4 36 7 212.3 3.4 5 0 32 330.4 10.1 5 3 6 234.7 3.4 4 32 6 184.4 2.8 4 36 8 248.6 3.6 5 1 0 468.3 7.0 5 3 7 43.6 4 32 7 147.4 2.6 4 36 9 84.3 4.1 5 I 1 435.9 6.6 5 3 8 349.2 4.6 4 32 8 112.8 2.6 4 36 10 60.3 4.9 5 1 2 334.9 6.6 5 3 9 615.3 9.9 4 32 9 150.4 2.8 4 36 11 126.2 3.0 5 1 3 437.9 6.8 5 3 10 140.9 3.1 4 32 10 86.0 3.5 4 36 12 186.3 3.2 5 1 4 248.8 3.4 5 3 11 299.9 4.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -123- 453.8 6.4 382.1 5.2 91.9 5.0 290.4 5.1 239.4 6.9 167.6 3.8 176.9 4.3 394.5 6.1 30.1 11.5 243.8 4.4 334.3 4.9 66.2 9.1 149.1 4.6 135.8 4.6 66.6 8.0 55.4 14.6 128.6 16.1 175.6 6.0 200.4 9.0 190.4 6.5 168.4 9.2 227.1 3.5 821.5 13.0 162.6 2.9 191.2 2.9 308.0 4.0 284.5 3.8 338.3 4.6 325.3 4.6 579.7 8.7 187.7 3.3 164.1 3.9 126.6 3.4 806.8 9.6 290.9 4.6 384.1 5.5 726.4 12.6 409.1 6.0 391.8 6.1 318.0 5.3 153.5 4.4 332.8 5.5 267.3 5.3 144.2 6.3 21.4 9.9 32.2 13.3 150.8 4.6 69.6 9.0 48.0 12.9 176.2 15.8 83.8 9.9 227.9 5.9 162.7 7.9 117.6 9.6 235.6 4.3 564.7 7.8 94.4 2.5 368.2 5.5 154.0 2.6 380.0 5.2 140.4 2.7 122.9 3.3 428.4 6.2 204.1 3.2 408.1 5.7 1 223.3 3.8 Z388.9 5.5 3574.4 8.8 4 390.6 5.7 500.7 7.4 404.2 6.3 7 140.0 6.3 75.0 9.2 442.1 6.0 258.1 4.6 265.7 4.7 76.7 8.2 30.0 11.9 113 .4 8.1 236.3 4.2 160.8 4.8 79.1 9.6 357.7 8.8 73.0 14.7 178.6 7.7 97.9 10.3 144.7 8.8 493.8 7.7 185.2 2.7 423.8 6.1 159.3 2.5 43.9 4.6 166.0 2.7 377.1 5.0 314.4 4.2 603.7 8.3 268.5 4.1 502.9 7.8 458.2 6.4 486.6 7.3 151.7 3.3 305.1 5.8 206.9 4.8 215.9 4.2 218.2 4.3 221.1 4.2 380.1 5.7 p78 .1 5.9 192.2 4.6 217.6 4.0 210.3 3.9 108.1 7.9 192.1 4.4 312.2 5.4 128.0 7.3 1367.4 13.0 186.4 5.3 143.1 7.6 1103.0 10.0 118.7 12.4 233.0 3.8 232.4 3.4 227.8 3.2 227.2 3.4 231.8 4.3 164.2 3.1 548.7 7.3 299.1 4.1 31.4 9.9 690.3 8.9 LI 114.2 3.6 1 549.2 8.1 2 161.2 3.3 3 154.9 3.2 4 273.5 5.1 5 594.3 8.3 6 424.9 5.9 7 304.1 4.9 8 215.4 4.5 9 233.0 4.8 0 225.7 3.8 1 97.0 7.4 2 387.2 5.6 3 324.7 4.9 176.2 4.2 45.5 13.2 297.2 4.8 118.3 7.5 246.4 11.8 118.3 9.3 141.3 9.1 117.3 8.4 92.9 12.2 232.5 3.9 426.4 6.4 345.1 4.8 96.4 2.6 67.8 3.3 239.2 4.0 200.8 3.0 340.6 4.9 387.0 4.9 234.5 3.4 390.2 6.7 226.1 3.8 260.7 4.0 267.1 4.4 522.5 7.0 183.5 5.8 328.7 5.1 536.7 8.6 142.0 6.8 209.2 4.1 271.3 4.4 110.2 4.9 210.4 6.0 20.7 9.7 153.0 4.8 244.4 5.2 108.9 5.7 68.9 9.5 144.3 10.2 244.0 5.3 I56.4 20.6 30.8 13.8 49.8 18.3 128.4 2.8 172.5 3.0 384.3 5.8 170.4 2.6 274.3 3.9 151.4 2.5 155.1 2.7 311.1 4.2 267.5 4.7 595.2 9.1 )279.3 4.1 1 539.4 8.1 Z 664.8 10.5 3 437.8 5.8 1 186.8 5.6 5 786.5 10.1 6 189.4 4.0 7 282.8 4.8 8 108.0 4.6 9 142.4 4.0 O 275.6 4.4 1 190.4 3.8 2 424.2 6.6 3 102.8 4.8 4 82.6 6.8 5 178.8 4.3 6 94.6 5.7 8 93.2 7.2 9 132.1 7.9 0 109.9 10.2 9 31 9 32 10 0 10 1 10 2 10 3 10 4 10 5 10 6 10 7 10 8 10 9 10 10 10 11 10 12 10 13 10 14 10 15 10 16 10 11 10 1 10 1s 10 2C 10 21 10 2Z 10 23- 10 24 10 2f 10 2( 10 2, 10 2 10 2S 10 3Y 10 31 10 3, 11 0 11 1 11 2 11 3 11 4 11 5 11 6 31.3 14.5 41.2 16.7 274.0 466.6 8.2 278.3 4.1 221.1 3.4 519.7 7.7 220.0 3.4 122.7 3.1 57.5 552.7 7.2 271.9 3.8 503.4 6.6 280.8 4.1 439.1 448.4 312.5 7.3 286.2 4.4 192.0 3.9 214.1 234.5 185.3 3.9 1 29.0 12.2 314.2 4.6 445.3 6.6 1125.7 [207.7 3.9 i212.3 131.7 5.1 219.0 10.7 1244.0 5.1 166.8 145.1 159.2 18.4 179.4 17.3 226.1 3.6 241.7 3.6 348.4 4.7 350.9 181.5 2.7 285.2 3.9 594.7 8.4 518.2 7.6 290.3 4.4 485.0 6.4 L166.8 2.9 1 309.1 4.7 2 121.2 6.3 3 292.8 4.9 4 222.9 4.7 5 81.2 5.1 6 373.0 5.9 7 57.9 8 325.6 5.3 9 275.6 4.4 0 159.5 3.9 1 164.9 4.7 2 105.0 3 153.0 4.1 4 113.7 5 91.8 6.8 6 290.4 5.6 .7 423.1 14.1 .8 144.9 5.7 :9 122.3 6.7 0o 217.6 6.7 1l 43.2 15.7 D 372.1 7.6 1 293.8 5.7 2 271.5 3.7 3 173.6 2.7 4 85.3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -124- 260.8 .3.6 409.0 6.1 572.7 8.0 380.4 5.2 42.2 7.9 497.4 7.3 211.1 3.6 247.5 3.8 491.9 7.3 301.9 4.6 437.1 6.3 484.3 7.1 235.3 4.0 208.9 3.8 248.6 4.2 207.2- 3.7 35.2 12.0 147.6 4.3 152.9 4.7 100.6 6.8 159.1 4.6 175.7 5.9 75.1 19.8 71.8 13.0 154.3 5.5 18.6 9.4 29.9 13.7 383.5 7.7 310.9 5.6 258.2 3.8 526.9 6.2 201.7 3.1 488.8 6.7 478.4 7.0 511.7 7.4 688.4 9.1 469.3 6.3 236.9 3.8 363.1 6.2 173.2 5.3 322.4 4.6 1 80.0 6.7 i493.3 7.7 213.4 3.8 1257.1 4.8 1287.2 4.9 116.1 4.5 69.9 6.9 1 263.1 4.0 Z166.1 3.6 3 99.0 5.8 4 64.3 8.6 149.1 4.6 34.3 15.6 7 120.4 6.7 9 168.2 5.6 135.9 6.7 D 33.6 14.7 1 46.6 15.3 437.5 7.7 482.7 8.5 472.6 6.7 1 872.3 12.1 1 483.7 7.3 i318.4 5.0 i687.5 9.1 1 374.6 4.7 3240.3 3.8 138.8 2.8 0 438.4 6.5 2 464.2 6.1 3 293.1 4.6 404.7 6.4 82.9 5.6 353.1 5.1 150.5 3.6 344.7 5.1 84.4 5.8 172.5 3.8 100.8 5.1 125.1 5.4 257.3 4.3 140.3 5.1 86.3 6.7 346.3 8.7 26.9 12.9 115.6 6.7 195.3 6.3 83.3 12.2 67.6 17.3 169.0 2.9 279.0 3.9 327.5 4.1 454.8 6.8 572.8 9.4 637.9 7.9 64.9 4.5 138.8 2.7 546.1 8.5 296.6 5.9 478.5 6.7 400.7 7.7 222.4 3.9 327.5 5.3 434.2 6.6 166.8 3.6 237.1 4.1 275.0 4.4 218.9 4.3 P163.5 3.7 129.1 4.2 61.9 8.4 117.5 5.4 57.1 8.6 169.5 4.4 i231.5 4.7 185.4 10.1 1176.5 6.3 47.4 16.2 52.8 15.6 94.6 9.2 239.5 4.8 754.2 20.6 231.4 3.1 307.9 3.9 358.1 5.0 399.1 6.6 734.9 8.4 275.2 4.0 334.9 7.0 I110.8 3.6 D 391.0 6.8 1 384.8 6.5 2 130.7 3.9 3 356.1 5.2 4 359.9 5.6 5 144.2 4.3 6 163.0 4.2 7 272.5 4.3 8 211.5 3.8 9 192.6 3.6 0 75.6 6.4 1 167.3 3.9 ,2 153.9 4.4 90.1 6.1 38.5 11.1 36.8 14.5 94.7 9.6 138.8 6.3 71.2 9.6 45.1 15.3 96.0 14.4 299.7 4.6 686.1 19.9 194.4 3.6 52.6 4.4 184.3 2.8 581.3 8.2 544.6 8.0 576.9 10.1 232.8 3.5 402.1 7.1 475.4 6.9 485.7 6.7 292.3 4.4 313.1 4.9 160.3 .3 392.7 6.4 517.2 7.1 133.2 4.3 187.5 3.7 241.7 4.0 135.2 3.9 72.7 6.1 46.0 12.5 158.3 4.3 162.8 4.8 427.2 12.9 117.8 7.9 90.3 9.1 52.7 12.2 73.2 9.5 137.0 8.7 609.2 9.8 345.0 7.0 546.7 9.0 419.4 5.8 88.4 7.4 381.6 7.0 315.2 4.2 445.6 7.7 86.9 8.4 133.1 3.2 721.6 10.8 257.1 3.8 218.6 3.9 1226.9 3.6 325.1 5.2 370.7 5.7 i195.4 4.4 41.0 9.7 1193.8 4.3 316.2 5.6 117.7 4.5 1 273.7 4.3 2 72.1 8.7 3 67.3 7.9 1 22.0 10.8 5 165.7 5.1 5 204.2 4.6 7 96.8 10.5 8 101.8 10.3 9 18.1 9.0 )221.8 5.8 1341.1 7.1 326.9 5.7 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 25 06 27 3 4 5 6 7 8 9 11 1: 1.

1i 1* 1* 2 2 2 12 12 112 309.9 48.7 5 136.9 390.9 51.6 6 461.0 157.1 338.9 183.2 115.1 154.6 150.4 264.4 148.4 35.9 1 188.9 164.7 189.6 289.4 63.6 55.21 253.1 105.1 150.5 190.1 69.8 172.1 652.5 182.8 213.7 605.6 615.0 725.2 101.5 133.7 401.4 57.3 0 297.7 1 460.1 2 334.6 3 236.0 4 66.9 5 100.1 6 57.6 7 148.7 8 219.3 9 91.2 0 152.5 1 65.1 2 150.8 3 19.9 5 226.3 6 39.4 7 165.6 8 98.3 0 731.5 1 482.1 2 259.5 3 250.2 4 292.2 5 629.1 6 145.7 7 416.8 8 396.8 9 252.4 .0 549.6 [1 313.2 12 295.2 13 61.7 14 102.5 I5 304.8 16 174.2 4.3 .8 .8 3.4 3.1 3.4 4.1 1.4 3.7 3.8 4.3 8.3 0.4 16.8 6.3 4.4 11.5 13.2 11.2 4.6 3.7 9.4 17.0 9.6 3.4 5.3 5.6 6.9 4.6 3.6 5.9 7.6 3.4 3.8 4.4 4.1 8.4 3.7 9.8 4.8 14.4 6.7 13.6 10.1 5.3 4.1 9.8 3.8 7.9 4.7 4.7 5.9 3.3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -125- 17 107.0 3.8 18 244.1 3.8 19 83.3 5.6 147.0 3.8 21 167.5 3.8 22 152.1 4.9 23 447.8 15.8 24 126.5 7.3 217.2 4.6 26 135.7 6.0 27 151.3 6.9 28 199.8 5.7 0 108.1 3.5 1 485.8 9.1 2 334.1 7.0 3 220.1 4.1 4 521.7 7.2 255.0 3.7 6 579.1 8.1 7 158.0 3.1 8 186.8 3.0 9 390.7 5.3 64.4 4.7 11 113.1 3.4 12 347.0 5.0 13 437.4 6.5 14 195.0 3.4 305.9 4.1 16 111.8 3.7 17 45.2 11.2 18 109.5 3.9 19 142.3 3.8 221.3 4.3 21 88.4 5.8 22 165.2 10.1 23 55.8 10.6 24 65.6 9.9 180.0 4.9 26 122.9 5.7 27 112.4 10.2 28 159.9 10.0 0 313.0 6.7 1 336.3 7.0 2 220.4 4.5 3 419.9 6.4 4 289.5 4.1 119.2 2.7 6 237.5 3.4 7 274.8 4.4 8 171.7 3.0 9 221.4 3.3 128.3 3.1 11 252.6 4.0 12 442.9 6.1 13 123.3 3.1 14 69.5 5.9 184.0 3.6 16 151.0 3.3 17 93.9 5.0 18 72.4 6.6 19 15.9 7.9 146.4 4.1 21 20.4 10.0 22 199.6 6.1 23 149.7 5.0 24 349.7 5.3 90.7 10.1 26 58.1 13.8 27 207.6 4.8 0 271.4 6.1 1 91.0 3.7 2 303.4 5.2 286.9 4.8 158.7 2.7 271.6 3.8 275.6 4.5 213.5 3.5 334.2 5.0 260.4 3.7 324.3 4.4 120.5 3.1 236.4 4.2 132.3 3.0 209.8 3.3 25.2 9.5 92.4 4.1 134.3 3.5 150.4 3.5 149.6 4.1 143.0 4.9 392.8 17.1 120.0 5.7 77.6 10.4 51.5 11.5 38.9 14.1 59.5 14.7 312.9 6.4 109.9 3.5 170.9 3.7 311.6 5.6 250.6 3.2 379.1 5.7 113.6 3.3 388.1 6.6 262.5 4.0 189.2 3.2 218.6 3.4 136.8 3.0 263.1 4.3 267.2 4.0 156.7 3.5 59.6 5.7 119.8 3.6 297.3 4.4 162.8 3.4 150.1 3.8 172.6 15.3 265.1 4.5 99.7 8.2 36.5 13.7 180.4 4.9 146.1 5.3 115.6 7.6 374.6 7.4 264.1 5.7 244.5 4.7 250.6 5.2 77.9 3.7 423.3 5.4 76.0 4.1 332.5 4.9 335.7 5.3 395.6 6.0 192.7 4.3 137.1 3.0 15.8 7.3 252.0 4.3 23.5 9.4 i206.7 3.8 117.5 3.6 114.5 3.8 1191.1 3.7 )21.4 10.4 )22.8 10.5 26 21 26 22 26 23 26 24 26 25 27 0 2 27 1 2 27 2 2 27 3 2 27 4 1 27 5 3 27 6 1 27 7 27 8 27 9 27 10 27 11 27 12 27 13 27 14 27 15 27 16 27 17 27 18 27 19 27 20 27 21 27 22 27 23 27 24 27 25 28 0 2 28 1 28 2 1 28 3 28 4 2 28 5 1 28 6 1 28 7 1 28 8 2 28 9 1 28 10 28 11 28 12 28 13 28 14 28 15 28 16 28 17 28 18 28 19 28 20 28 21 28 22 28 23 28 24 29 0 29 1 29 2 29 3 29 4 29 5 29 6 29 7 29 8 29 9 29 10 29 11 29 12 29 13 29 14 29 15 139.1 90.6 93.1 106.9 149.0 98.9 47.6 55.8 26.0 05.2 71.0 03.5 13.1 18.8 50.7 213.8 93.7 137.6 157.6 57.9 51.8 202.7 137.1 272.6 85.0 28.4 68.2 37.9 115.4 116.2 61.0 56.6 63 .8 72.1 40.5 45.1 24.6 23.6 80.7 ~56.3 57.1 295.4 165.5 249.5 75.5 132.0 16.7 169.3 66.5 187.1 179.6 166.9 126.0 183.5 240.7 22.7 40.2 101.3 171.1 227.7 135.9 74.7 154.7 261.8 124.5 66.1 59.6 113.3 84.4 67.5 62.5 120.4 4.6 6.5 5.8 5.7 6.1 5.8 4.2 4.4 4.7 2.6 4.8 2.4 6.3 8.2 5.4 3.4 3.2 2.9 3.1 5.6 7.7 3.5 3.7 4.5 11.2 11.8 6.6 11.4 7.6 6.8 11.8 6.0 3.5 3.5 6.1 3.6 2.4 2.6 3.0 3.8 3.0 4.2- 4.1 3.8 5.3 3.7 7.9 3.4 8. 1 8.3 4.3 3.7 4.6 4.5 5.8 10.9 4.8 5.3 3.7 4.4 2.7 3.1 2.5 3.6 2.7 3.8 5.0 3.0 4.2 4.0 5.7 4.0 113.9 6.4 168.0 6.9 13.5 6.8 92.0 55.7 7.9 149.4 4.6 176.7 66.7 10.0 124.3 3.2 253.6 132.6 2.7 197.8 3.6 130.6 2.8 315.0 4.9 318.2 4.2 158.4 2.6 84.7 113.6 2.9 364.9 183.4 83.3 3.9 127.5 3.2 75.5 5.3 31.5 14.8 15.6 7.8 122.1 3.8 71.8 6.2 72.6 7.3 187.3 4.1 29.7 12.6 46.8 11.0 82.0 3.1 227.6 3.9 161.8 215.9 119.1 364.2 238.2 3.6 262.6 3.8 175.3 3.1 62.8 4.8 58.0 4.3 126.8 3.4 114.1 3.4 159.9 5.4 312.6 9.3 205.3 4.2 90.2 132.1 4.3 211.7 3.8 53.6 I79.8 7.1 93.1 3.1 201.7 3.8 219.1 4.2 188.5 124.2 3.2 121.9 2.6 159.7 2.7 153.3 2.6 61.8 4.3 162.1 3.1 I100.8 3.1 154.0 3.4 106.1 6.6 1214.0 11.2 1 182.2 3.9 5157.6 3.6 i47.9 9.4 7155.6 3.9 354.7 123.1 4.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -126- 111.8 4.8 21 49.8 13.1 0 227.4 4.2 1 68.6 3.1 2 157.7 3.6 3 155.6 3.1 4 156.0 3.2 13.5 6.5 6 165.6 3.2 7 76.9 4.2 8 98.5 2.9 9 90.9 3.3 18.1 8.6 11 259.0 7.9 12 140.9 4.2 13 316.6 4.3 14 132.1 3.6 125.0 3.6 16 101.9 5.1 17 80.1 6.9 18 58.0 9.0 19 57.0 8.2 81.6 10.6 0 151.6 4.6 1 169.1 3.2 2 131.7 2.9 3 25.8 8.4 4 162.1 3.2 44.3 6.0 6 186.4 3.1 7 175.2 3.0 8 219.8 5.5 9 237.4 7.2 69.2 7. 3 11 48.9 6.1 12 33.0 10.9 13 120.2 4.1 14 165.9 3.8 80.3 5.7 16 232.1 4.0 17 16.6 8.1 18 194.3 6.0 0 42.9 7.1 1 95.7 4.4 2 172.3 5.0 3 202.8 3.9 4 51.3 5.9 149.2 4.9 6 199.1 6.5 7 146.7 7.1 8 45.9 5.8 9 287.4 4.1 113.6 3.2 11 113.3 4.5 12 241.0 4.3 13 67.3 6.9 14 167.0 3.8 91.5 4.8 16 68.3 8.5 17 62.6 6.1 1 189.1 10.1 2 385.8 9.9 3 253.3 7.7 4 17.3 7.9 260.0 4.9 6 161.8 3.9 7 183.0 3.4 8 105.0 3.3 9 133.4 3.0 108.0 3.8 11 130.2 3.7 12 93.0 4.0 13 164.0 3.5 14 59.4 6.8 15 50.4 8.3 16 55.9 8.8 0 227.0 8.0 1 194.4 6.5 2 86.7 4.2 3 136.4 5.3 4 33.7 7.3 5 150.1 3.4 6 103.9 3.9 7 80.3 4.0 8 190.4 3.0 9 141.5 2.7 10 82.6 3.8 11 139.6 3.2 12 154.5 3.4 13 228.1 4.0 14 170.2 3.7 15 60.3 10.9 2 165.6 5.3 4 160.3 3.3 5 108.2 3.1 6 268.2 5.4 7 163.6 3.7 8 86.2 3.1 9 114.4 2.8 10 149.8 3.2 11 121.4 3.3 12 86.7 4.1 13 62.2 7.1 1 82.5 4.1 2 148.1 5.1 3 154.6 5.4 4 166.3 5.7 5 88.7 6.2 6 28.0 11.6 7 84.1 2.9 8 117.8 310 9 66.6 4.2 10 60.7 4.7 11 203.2 4.6 2 20.0 8.6 5 224.1 5.2 6 213.8 4.7 7 80.1 4.1 8 60.8 4.6 9 17.3 8.1 4 119.3 4.7 5 139.1 5.0 0 102.9 3.6 1 194.6 4.4 2 210.0 4.2 3 430.1 9.3 4 471.7 14.4 5 123.2 3.9 6 58.9 7.8 7 431.0 9.0 8 74.9 6.5 11 361.2 8.0 12 15.8 11.0 13 201.8 5.4 14 84.5 20.7 15 197.1 11.9 17 507.6 12.8 18 66.6 22.5 19 250.3 6.1 20 235.0 6.6 21 451.4 8.7 22 70.8 9.4 61.8 17.0 231.8 9.5 42.0 19.5 90.7 8.2 93.3 8.6 196.5 19.1 60.4 20.2 85.8 16.1 28.1 18.1 26.6 18.0 456.4 6.3 284.4 4.0 336.2 4.6 228.1 3.5 201.2 3.1 262.4 4.4 179.3 2.7 192.6 3.7 345.0 4.4 115.8 2.8 377.2 6.1 181.8 3.4 252.7 4.0 142.3 3.3 218.7 5.1 275.5 8.4 349.9 5.5 244.4 4.7 244.9 4.2 258.1 4.6 129.2 5.9 120.1 5.3 168.4 4.1 105.2 7.2 45.6 11.9 77.1 8.4 72.4 9.1 112.6 5.5 136.5 18.7 143.2 5.7 183.6 5.8 76.0 11.3 224.6 5.8 334.4 4.8 275.0 3.9 284.0 3.9 75.3 3.0 402.6 6.7 231.2 3.3 446.1 6.9 252.9 3.6 317.3 4.6 461.7 6.7 440.8 6.4 331.9 5.1 320.6 4.7 101.3 4.2 290.7 5.9 482.8 7.5 915.0 13.4 157.8 4.8 138.6 5.2 234.9 4.2 149.0 5.5 229.5 4.4 79.3 6.2 1213.6 4.2 130.0 11.8 88.2 7.8 132.9 5.6 39.4 13.1 135.4 14.8 PCT/GB98/02542 2 29 95.8 2 30 62.5 17.0 2 31 184.7 7.1 2 32 84.5 10.2 3 0 100.0 2.6 3 1 129.3 2.7 3 2 218.0 3.4 3 3 436.8 5.8 3 4 166.5 2.9 3 5 517.3 3 6 129.2 3.1 3 7 147.5 3.4 3 8 229.7 3 9 235.8 4.1 3 10 89.5 5.8 3 11 301.9 5.3 i3 12 572.8 8.1 3 13 120.0 3 14 478.6 6.4 3 15 405.6 11.0 3 16 357.9 5.3 i3 17 243.8 4.7 3 18 330.9 5.4 3 19 169.0 i3 20 294.5 4.9 3 21 141.1 4.1 3 22 257.2 4.3 i3 23 178.6 i3 24 128.5 4.8 3 25 49.6 13.0 i3 26 79.2 7.3 i3 27 73.1 7.9 i3 28 34.8 15.6 i3 29 102.7 7.3 i3 30 301.1 5.7 i 3 31 109.4 8.9 i 3 32 34.5 15.4 S4 0 40.7 4.4 5 4 1 124.6 5 4 2 67.3 3.4 5 4 3 491.9 8.6 5 4 4 247.5 5 4 5 295.0 4.3 5 4 6 429.5 5 4 7 144.7 3.3 5 4 8 619.6 5 4 9 294.3 5 4 10 646.6 10.0 5 4 11 408.1 6.2 5 4 12 422.1 5.7 5 4 13 183.3 4.8 5 4 14 501.6 7.4 5 4 15 624.7 9.2 6 4 16 520.6 7.8 6 4 17 244.8 4.4 6 4 18 257.6 5.3 6 4 19 287.1 6 4 20 362.1 6 4 21 130.0 5.4 6 4 22 251.1 6 4 23 26.8 11.3 6 4 24 207.4 4.3 6 4 25 147.2 4.8 6 4 26 143.5 4.3 6 4 27 76.6 8.9 6 4 28 111.1 7.6 6 4 29 47.6 13.5 6 4 30 177.0 6 4 31 87.9 9.7 6 4 32 33.8 15.1 6 5 0 93.9 2.6 6 5 1 191.1 3.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -127- 6 5 2 195.9 2.9 6 7 9 319.9 4.8 6 9 16 245.2 4.9 6 11 24 246.0 4.3 6 5 3 264.5 4.2 6 7 10 169.2 3.2 6 9 17 239.7 3.9 6 11 25 157.9 5.2 6 5 4 321.7 4.7 6 7 11 285.8 4.2 6 9 18 448.1 7.1 6 1126 142.0 9.1 6 5 5 219.8 3.3 6 7 12 494.0 7.0 6 9 19 257.5 4.8 6 11 27 146.6 7.7 6 5 6 341.7 4.5 6 7 13 216.7 4.3 6 9 20 328.5 5.4 6 11 28 217.4 4.9 6 5 7 330.5 4.8 6 7 14 653.1 10.0 6 9 21 68.2 7.1 6 11 29 189.0 5.4 6 5 8 117.9 3.3 6 7 15 513.8 7.2 6 9 22 195.9 4.0 6 11 30 77.5 10.5 6 5 9 497.4 6.9 6 7 16 189.1 4.1 6 9 23 325.0 5.2 6 11 31 164.9 6 5 10 235.4 4.0 6 7 17 140.1 4.5 6 9 24 31.1 12.1 6 12 0 596.3 11.5 6 5 11 680.9 10.7 6 7 18 264.6 4.6 6 9 25 153.9 4.5 6 12 1 124.0 2.9 6 5 12 347.9 4.9 6 7 19 127.5 4.0 6 9 26 93.6 7.4 6 12 2 202.9 3.2 6 5 13 211.7 4.9 6 7 20 69.2 8.9 6 9 27 142.1 14.9 6 12 3 508.0 7.4 6 5 14 199.8 4.0 6 7 21 146.5 4.4 6 9 28 53.6 11.9 6 12 4 222.1 3.4 6 5 15 620.5 9.8 6 7 22 150.7 4.5 6 9 29 88.5 10.9 6 12 5 362.0 5.4 6 5 16 339.3 5.7 6 7 23 49.1 15.3 6 9 30 36.5 15.4 6 12 6 165.6 6 5 17 208.7 4.6 6 7 24 25.3 11.2 6 9 31 32.3 14.7 6 12 7 563.1 9.1 6 5 18 276.9 4.3 6 7 25 131.5 5.6 6 10 0 54.0 4.3 6 12 8 129.9 6 5 19 117.4 6.4 6 7 26 103.6 6.5 6 10 1 156.9 3.1 6 12 9 383.8 6 5 20 263.7 4.5 6 7 27 190.2 13.8 6 10 2 362.2 5.3 6 12 10 580.8 10.0 6 5 21 86.3 6.0 6 7 28 78.5 9.5 6 10 3 113.7 3.4 6 12 11 64.7 8.1- 6 5 22 44.1 10.8 6 7 29 143.4 7.1 6 10 4 149.2 3.2 6 12 12 433.2 7.2 6 5 23 171.4 4.5 6 7 30 166.4 6.7 6 10 5 322.8 4.7 6 12 13 275.5 4.8 6 5 24 66.6 8.7 6 7 31 114.2 12.9 6 10 6 917.1 12.1 6 12 14 90.3 6.2 6 5 25 192.8 5.6 6 7 32 90.6 12.3 6 10 7 769.7 10.2 6 12 15 237.7 5.4 6 5 26 114.4 5.5 6 8 0 94.8 2.3 6 10- 8 62.5 5.9 6 12 16 102.6 5.2 6 5 27 150.2 6.1 6 8 1 110.8 3.3 6 10 9 245.4 3.5 6 12 17 68.2 8.8 6 5 28 96.3 7.9 6 8 2 336.1 5.2 6 10 10 87.4 3.9 6 12 18 250.8 4.3 6 5 29 169.6 5.0 6 8 3 251.7 3.6 6 10 11 312.4 4.5 6.12 19 315.1 4.7 6 5 30 162.8 6.1 6 8 4 177.0 2.9 6 10 12 190.9 3.9 6 12 20 28.5 11.5 6 5 31 76.7 14.0 6 8 5 123.1 2.6 6 10 13 268.4 8.6 6 12 21 197.1 4.7 6 5 32 181.2 5.8 6 8 6 227.4 3.7 6 10 14 63.2 8.2 6 12 22 64.5 7.7 6 6 0 251.6 3.9 6 8 7 477.5 7.2 6 10 15 527.9 7.8 6 12 23 110.7 5.6 6 6 1 460.7 8.3 6 8 8 187.9 3.1 6 10 16 247.4 4.8 6 12 24 362.2 6.2 6 6 2 100.9 2.6 6 8 9 399.9 6.0 6 10 17 123.0 5.0 6 12 25 123.8 5.8 6 6 3 137.2 2.6 6 8 10 364.3 5.3 6 10 18 293.4 4.6 6 12 26 280.5 9.4 6 6 4211.3 3.1 6 811 281.4 4.5 6 1019 167.4 4.0 6 1227 112.7 6.9 6 6 5 185.2 3.2 6 8 12 285.8 5.1 6 10 20 251.5 4.2 6 12 28 162.2 6.8 6 6 6 340.1 4.8 6 8 13 592.0 8.7 6 10 21 203.5 4.1 6 12 29 170.0 10.1 6 6 7 85.7 3.0 6 8 14 314.7 5.3 6 10 22 236.6 4.4 6 12 30 108.2 8.8 6 6 8 244.0 3.6 6 8 15 63.0 7.8 6 10 23 61.3 7.4 6 12 31 320.4 7.7 6 6 9 19.6 8.3 6 8 16 679.4 9.6 6 10 24 119.9 5.6 6 13 0 797.0 13.4 6 6 10 470.1 7.1 6- 8 17 200.3 4.0 6 10 25 69.2 7.3 6 13 1 577.5 11.5 6 6 11 632.3 9.9 6 8 18 130.0 4.2 6 10 26 32.4 13.1 6 13 2 222.0 3.2 6 6 12 246.9 3.8 6 8 19 434.7 7.4 6 10 27 23.0 11.4 6 13 3 489.6 6 6 13 290.9 5.2 6 8 20 168.4 4.3 6 10 28 156.6 4.9 6 13 4 347.1 4.6 6 6 14 40.1 15.0 6 8 21 132.8 4.4 6 10 29 105.4 7.4 6 13 5 327.8 4.7 6 6 15 525.6 8.3 6 8 22 244.4 5.2 6 10 30 243.4 5.6 6 13 6 198.8 6 6 16 198.7 4.9 6 8 23 161.6 4.6 6 10 31 55.5 16.2 6 13 7 684.3 11.0 6 617 145.0 5.1 6 824 38.4 13.1 6 11 0 354.4 5.3 6 13 8172.7 3.1 6 6 18 24.4 11.6 6 8 25 117.1 5.7 6 11 1 467.5 8.4 6 13 9 149.4 5.2 6 6 19 524.1 8.5 6 8 26 20.2 9.8 6 11 2 250.3 3.8 6 13 10 527.8 6.4 6 A6 20 142.0 5.1 6 8 27 270.9 8.8 6 11 3 448.3 6.2 6 13 11 415.9 14.7 6 6 21 352.8 5.2 6 8 28 90.9 7.1 6 11 4 53.1 4.5 6 13 12 187.6 3.9 6 6 22 144.0 4.7 6 8 29 256.8 4.7 6 11 5 301.5 4.0 6 13 13 138.6 3.9 6 6 23 125.9 5.6 6 8 30 143.7 6.6 6 11 6 383.9 5.6 6 13 14 558.4 6 6 24 240.9 4.4 6 8 31 184.2 6.2 6 11 7 270.0 3.8 6 13 15 255.6 4.9 6 6 25 23.1 10.8 6 9 0 280.4 4.0 6 11 8 364.0 4.9 6 13 16 267.9 4.3 6 6 26 181.4 4.2 6 9 1 270.1 4.6 6 11 9 444.4 6.1 6 13 17 168.2 3.6 6 6 28 53.9 15.0 6 9 2 339.6 4.6 6 11 10 575.4 8.6 6 13 18 138.5 3.9 6 6 29 369.9 6.1 6 9 3 214.6 3.6 6 11 11 473.2 7.3 6 13 19 298.8 6 6 30 125.7 7.3 6 9 4 371.8 5.5 6 11 12 25.1 12.3 6 13 20 323.9 6 6 31 183.4 5.4 6 9 5 28.1 8.5 6 11 13 563.4 8.6 6 13 21 68.7 7.1 6 6 32 48.9 16.2 6 9 6 317.7 4.7 6 11 14 139.6 4.4 6 13 22 115.3 4.8 6 7 0 138.9 3.9 6 9 7 345.6 4.4 6 11 15 486.3 8.0 6 13 23 48.6 11.2 6 7 1 264.7 4.4 6 9 8 319.4 4.8 6 11 16 365.6 5.2 6 13 24 289.2 6 7 2 206.2 3.2 6 9 9 426.3 5.7 6 11 17 209.2 4.7 6 13 25 15.8 6 7 3 85.6 3.1 6 9 10 389.6 4.6 6 11 18 176.3 4.0 6 13 26 120.1 20.0 6 7 4 225.7 3.1 6 9 11 647.5 9.3 6 11 19 221.0 4.6 6 13 27 96.3 10.0 6 7 5 294.4 4.4 6 9 12 263.0 5.1 6 11 20 317.5 5.1 6 13 28 25.3 11.9 6 7 6 372.6 5.7 6 9 13 250.9 5.7 6 11 21 59.4 7.8 6 13 29 92.7 11.0 6 7 7 487.7 6.4 6 9 14 618.1 8.1 6 11 22 217.7 4.0 6 13 30 118.0 7.9 6 7 8 234.1 3.5 6 9 15 287.2 5.0 6 11 23 181.1 4.2 6 14 0 535.9 8.3 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -128- 6 14 1 232.1 .4.1 6 16 11 423.5 6.1 6 18 25 172.2 6.1 6 21 9 301.2 6 14 2 588.0 8.0 6 16 12 452.4 6.6 6 18 26 147.5 4.6 6 21 10 333.6 4.9 6 14 3 696.4 10.3 6 16 13 356.2 4.9 6 18 27 159.4 5.1 6 21 11 142.2 3.3 6 14 4 431.8 8.1 6 1614 375.8 5.5 6 18 28 121.5 10.3 6 21 12 182.2 3.4 6 14 5 381.2 4.8 6 16 15 370.5 5.9 6 18 29 57.5 13.7 6 21 13 185.2 3.6 6 14 6 287.2 4.5 6 16 16 252.9 4.1 6 19 0 435.7 8.1 6 21 14 48.2 7.4 6 14 7 274.8 4.1 6 16 17 216.5 3.9 6 19 1 139.8 4.5 6 21 15 208.6 3.9 6 14 8 224.1 4.9 6 16 18 124.4 4.1 6 19 2 112.4 8.2 6 21 16 83.0 4.4 6 14 9 214.3 5.8 6 16 19 262.2 4.3 6 19 3 404.6 12.1 6 21 17 133.8 3.8 6 14 10 636.9 13.6 6 16 20 83.2 5.4 6 19 4 648.5 9.5 6 21 18 86.8 5.9 6 14 11 586.3 7.8 6 16 21 38.5 11.6 6 19 5 467.8 6.4 6 21 19 60.5 12.8 6 14 12 384.4 6.4 6 16 22 199.0 4.1 6 19 6 666.5 11.9 6 21 20 114.5 6 14 13 490.0 6.9 6 16 23 165.3 3.9 6 19 7 273.8 5.4 6 21 21 99.6 4.8 6 14 14 440.0 6.7 6 16 24 35.4 13.3 6 19 8 219.9 3.8 6 21 22 113.4 22.0 6 14 I5 155.4 4.5 6 16 25 80.7 8.7 6 19 9 560.4 8.1 6 21 23 293.2 4.8 6 14 16 275.1 4.1 6 16 26 42.5 14.6 6 19 10 532.7 7.6 6 21 24 84.2 7.2 6 14 17 286.9 4.7 6 16 27 95.1 8.5 6 19 11 234.1 3.9 6 21 25 156.0 6.7 6 14 18 315.6 5.1 6 16 28 103.0 7.2 6 19 12 198.4 3.6 6 2126 105.1 7.3 6 14 19 224.0 4.4 6 16 29 79.1 9.8 6 19 13 374.0 5.3 6 21 27 80.5 11.8 6 14 20 201.1 4.1 6 17 0 389.9 7.0 6 19 14 256.5 4.1 6 22 0 364.6 7.2 6 14 21 96.2 6.2 6 17 1 421.6 7.1 6 19 15 84.7 5.1 6 22 1 421.5 7.4 6 14 22 221.4 4.0 6 17 2 363.1 7.9 6 19 16 124.7 3.6 6 22 2 169.7 4.4 6 14 23 149.1 5.5 6 17 3 65.9 7.3 6 19 17 114.0 3.4 6 22 3 512.3 6 14 24 105.7 6.0 6 17 4 244.9 5.2 6 19 18 278.5 4.6 6 22 4 323.7 4.4 6 14 25 135.3 6.0 6 17 5 326.7 5.1 6 19 19 163.3 3.8 6 22 5 102.3 3.3 6 14 26 15.5 7.9 6 17 6 252.4 4.1 6 19 20 165.6 3.7 6 22 6 260.2 3.7 6 14 27 40.6 14.4 6 17 7 481.1 15.6 6 19 21 124.3 5.6 6 22 7 77.5 3.7 6 14 28 166.3 5.7 6 17 8 72.2 5.0 6 19 22 154.7 4.3 6 22 8 191.8 4.2 6 14 29 55.0 14.6 6 17-9 262- *6 5.6 6 19 23 47.7 19.5 6 22 9 89.1 6 14 30 117.0 9.5 6 17 10 403.3 6.2 6 19 24 64.3 13.0 6 22 10 76.6 4.2 6 15 0 237.0 3.7 6 17 11 282.1 4.6 6 19 25 137.5 4.5 6 22 11 170.8 3.3 6 15 1 582.0 10.8 6 17 12 85.1 4.2 6 19 26 23.4 11.0 6 2212 198.2 6 15 2 240.5 3.7 6 17 13 323.3 5.3 6 19 27 159.0 5.3 6 22 13 100.2 3.8 6 15 3 227.9 3.4 6 17 14 241.1 4.6 6 19 28 180.6 5.4 6 22 14 170.3 3.3 6 15 4 1110.5 15.0 6 17 15 277.1 4.2 6 20 0 455.8 8.9 6 22 15 70.9 4.7 6 15 5 648.3 9.5 6 17 16 71.2 6.2 6 20 1 348.4 7.3 6 22 16 262.5 3.8 6 15 6 123.4 3.3 6 17 17 139.7 3.5 6 20 2 191.0 3.4 6 22 17 90.6 4.3 6 15 7 541.8 8.5 6 17 18 97.7 5.0 6 20 3 324.6 4.9 6 22 18 109.3 4.3 6 15 8 214.2 4.1 6 1719 119.7 4.0 6 20 4 175.4 3.5 6 22 19247.1 4.3 6 15 9 90.0 8.5 6 17 20 167.9 4.4 6 20 5 462.1 6.0 6 22 20 188.0 4.6 6 I5 10 291.3 4.4 6 17 21 102.2 5.0 6 20 6 324.8 5.2 6 22 21 123.9 5.6 6 15 11 250.6 4.2 6 17 22 171.3 4.0 6 20 7 237.8 4.2 6 22 22 23.6 11.8 6 15 12 509.4 7.5 6 17 23 152.0 5.4 6 20 8 315.1 4.8 6 22 23 93 .9 6 15 13 36.5 9.1 6 17 25 77.3 11.4 6 20 9 163.4 3.5 6 22 24 75.9 8.1 6 15 14 338.0 5.3 6 17 26 41.8 13.9 6 20 10 240.1 4.5 6 22 25 77.4 6 15 15 140.0 3.6 6 17 27 210.1 5.1 6 20 11 341.0 4.8 6 22 26 80.7 9.1 6 15 16 39.7 10.5 6 17 28 134.8 10.5 6 20 12 32.3 9.9 6 22 27 65.9 12.3 6 15 17 18.2 8.6 6 17 29 155.3 6.1 6 20 13 286.5 4.8 6 23 0 143.2 3.7 6 15 18 136.3 4.0 6 18 0 223.1 6.0 6 20 14 18.8 8.5 6 23 1 256.2 4.6 6 15 19 159.5 4.1 6 18 1 269.6 5.9 6 20 15 81.6 4.5 6 23 2 195.3 4.2 6 15 20 232.4 4.0 6 18 2 449.4 6.9 6 20 16 207.0 3.5 6 23 3 181.8 3.7 6 1-5 21 77.9 6.2 6 18 3 228.5 3.4 6 20 17 246.6 3.8 6 23 4 135.7 2.6 6 15 22 94.9 7.9 6 18 4 194.0 3.1 6 20 18 150.2 3.4 6 23 5 255.1 3.9 6 15 23 146.6 4.7 6 18 6 280.0 8.2 6 20 19 170.1 4.0 6 23 6 129.7 2.9 6 15 24 52.4 10.2 6 18 7 82.7 4.7 6 20 20 196.9 3.7 6 23 7 303.0 4.6 6 15 25 286.1 12.3 6 18 8 328.8 5.3 6 20 21 117.0 4.7 6 23 8 63.8 4.7 6 15 26 189.6 5.0 6 18 9 151.3 3.7 6 20 22 29.0 11.9 6 23 9 464.8 8.3 6 15 27 101.8 6.9 6 18 10 268.7 4.7 6 20 23 193.0 23.3 6 23 10 114.2 4.3 6 15 28 85.2 10.9 6 18 11 144.5 3.9 6 20 24 119.0 5.9 6 23 11 325.5 4.6 6 15 29 111.8 7.3 6 18 12 25.5 10.6 6 20 25 139.5 5.3 6 23 12 315.3 4.3 6 15 30 124.0 7.1 6 18 13 41.2 10.5 6 20 26 118.1 8.4 6 23 13 348.7 6 16 0 243.3 5.1 6 18 14 212.8 3.6 6 20 27 29.4 13.5 6 23 14 274.2 4.6 6 16 1 149.7 3.4 6 18 15 240.0 4.2 6 20 28 67.0 10.6 6 23 15 279.9 6 16 2 195.1 3.1 6 18 16 119.6 3.7 6 21 0 101.1 3.3 6 23 16 74.2 6 16 3 391.1 5.2 6 18 17 44.9 11.2 6 21 1 246.3 4.1 6 23 17 136.7 4.6 6 16 4 441.4 6.1 6 18 18253.9 4.1 6 21 2 194.1 3.9 6 23 18 125.8 3.8 6 16 5 437.0 6.9 6 18 19 126.6 3.9 6 21 3 403.0 10.8 6 23 19 250.8 4.1 6 16 6 435.9 7.2 6 18 20 137.8 4.2 6 21 4 260.3 4.0 6 23 20 83.3 5.6 6 16 7 83.8 5.1 6 18 21 125.2 4.4 6 21 5 175.8 3.1 6 23 21 293.6 13.9 6 16 8 291.9 8.1 6 18 22 126.7 5.2 6 21 6 591.2 8.7 6 23 22 35.5 12.0 6 16 9 160.3 5.6 6 18 23 18.4 9.1 6 21 7 120.5 3.0 6 23 23 118.2 6 16 10 354.2 5.2 6 18 24 159.7 15.5 6 21 8 369.0 5.1 6 23 24 162.9 4.9 SUBSTiTUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -129- 106.1 6.3 26 72.6 13.9 0 255.5 4.8 1 355.3 6.6 2 247.0 4.3 3 274.9 5.9 4 353.9 4.7 145.6 2.9 6 326.9 4.5 7 172.1 3.4 8 415.4 6.6 9 157.2 2.9 87.6 5.9 11 29.1 10.0 12 54.8 6.5 13 58.7 5.6 14 172.7 3.9 287.8 4.6 16 235.6 4.0 17 180.1 3.4 18 231.3 3.9 19 71.9 6.1 214.7 15.3 21 17.3 8.5 22 82.9 7.7 23 173.1 4.8 24 217.6 4.8 99.1 7.2 26 23.3 10.9 0 134.1 4.5 1 56.3 7.4 2 278.2 7.4 3 229.6 5.4 4 373.6 6.0 332.8 4.5 6 279.1 4.1 7 108.1 3.3 8 134.3 2.7 9 109.0 3.2 264.2 3.9 11 206.7 3.4 12 379.7 5.7 13 338.9 5.4 14 92.1 4.5 104.9 3.7 16 115.6 4.6 17 101.9 5.6 18 43.7 10.8 110.3 6.3 21 132.1 4.4 22 72.7 6.4 23 266.0 5.9 24 55.8 14.1 75.2 8.0 0 126.6 3.2 1 526.5 12.4 i2 41.8 8.8 i3 75.8 6.3 i4 161.8 3.1 253.7 3.6 S6 229.3 3.5 37 329.2 4.5 8 413.5 5.2 9 162.0 3.0 10 334.8 4.9 11 212.9 3.3 12 17.9 8.4 13 337.8 5.3 14 53.8 6.2 15 181.0 3.5 6 16 67.6 6.2 6 17 104.6 5.1 208.6 4.7 92.9 7.9 39.6 11.3 14.1 7.1 21.1 10.1 135.3 7.3 54.8 12.8 26.3 12.6 380.2 6.5 593.7 10.9 156.9 3.6 269.7 5.5 257.5 4.3 263.0 3.8 163.9 2.9 48.5 5.3 190.0 2.7 107.2 3.9 271.1 4.1 117.4 3.3 233.1 3.6 131.1 3.4 102.5 4.8 93.5 4.0 67.1 7.6 188.6 4.2 272.0 9.5 136.9 4.5 137.5 4.6 163.2 4.6 58.2 11.9 40.9 12.6 41.1 14.7 321.8 5.7 62.3 4.5 82.4 3.7 93.4 3.4 141.4 3.2 234.0 3.7 158.1 2.7 161.0 2.8 218.9 3.4 112.4 3.2 83.4 3.8 1 130.2 3.5 !208.7 3.6 3 135.1 3.5 1 121.4 3.3 5 188.7 3.5 5 85.4 5.0 7 155.5 17.2 9 99.1 5.0 102.9 4.9 51.6 9.6 1 154.1 4.5 2 196.7 4.5 3 49.7 14.9 1 69.7 3.8 171.3 3.7 t186.4 3.9 306.7 6.0 1491.6 9.0 5203.6 3.1 i103.2 2.7 7 196.9 2.9 3185.1 2.8 139.6 3.0 0 284.5 4.6 1 154.7 3.5 2 170.5 3.1 3 108.4 3.3 4 57.2 6.9 147.2 13.3 146.1 3.5 60.4 7.6 150.8 3.7 142.6 4.0 111.1 5.9 130.9 4.4 192.6 4.0 67.8 4.2 221.6 3.8 292.1 5.3 91.1 3.5 280.9 4.7 115.7 3.1 136.4 2.6 54.5 5.0 159.2 3.2 171.1 2.9 225.4 3.6 80.2 3.9 75.9 4.6 161.9 8.4 156.8 3.6 103.3 4.4 231.4 4.6 95.6 5.6 81.5 6.7 82.2 7.4 18.7 9.4 242.3 4.8 174.8 3.5 78.3 4.1 200.7 4.0 237.9 4.9 214.8 3.8 93.3 2.9 136.6 2.7 106.0 3.2 207.2 3.7 I116.2 3.8 81.2 5.0 79.0 5.9 269.6 12.4 150.4 3.8 i193.8 3.5 94.1 5.1 154.6 4.0 3233.5 4.2 36.9 10.5 72.8 6.5 1 47.6 14.1 252.4 5.3 60.2 4.5 144.0 3.0 129.3 3.1 105.7 3.2 53.8 6.1 46.9 5.9 142.9 2.9 191.0 3.2 139.9 3.0 0 178.0 3.0 1 92.9 9.7 2 136.9 8.4 3 174.9 3.7 4 62.7 6.7 5 195.7 4.5 6 38.7 10.5 7 169.6 4.6 8 82.5 5.3 9 112.8 4.8 ,0 85.0 8.9 126.3 73.7 4.1 223.3 4.4 251.6 4.9 243.5 4.8 122.6 3.4 143.5 2.9 156.0 13.5 6.6 94.3 11.7 118.3 11.6 143.2 3.3 30.2 10.6 167.5 3.4 164.8 4.1 218.1 16.5 295.0 4.6 99.2 9.2 29.6 12.5 354.7 6.2 254.4 4.7 275.0 5.8 112.0 .3.4 243.3 4.4 110.8 4.3 87.6 7.1 279.9 8.2 71.3 239.4 4.3 56.0 6.6 65.0 4.8 41.0 9.2 87.4 4.8 128.6 3.6 93.9 5.2 273.0 4.8 100.9 1135.3 5.6 146.3 3.4 98.0 8.8 290.6 11.6 249.6 7.8 128.8 113.2 3.4 39.8 8.1 189.0 185.4 3.3 )320.9 5.3 1 151.3 3.9 2 133.1 3.8 3 91.6 4l 64.3 5.6 5 103.3 4.4 6 132.5 1 14.4 6.8 180.7 96.4 142.8 3.8 1 97.1 3.9 5 112.3 3.1 i76.3 7 290.9 4.8 3177.6 17.5 7.9 0 138.5 1 109.7 3.7 2 17.2 3 202.8 3.8 4 179.5 4.3 5 60.6 9.4 0 18.4 7.7 SUBSTITUTE SHEET (RULE 26) WO 99/1 0379 130- 6 37 1 89.4 4.4 6 37 2 140.1 3. 5 6 37 3 184.5 3.9 6 37 4 312.9 6.4 6 37 5 193.3 4.3 6 37 6 199.4 3.9 6 37 7 14.9 7.2 6 37 8 102.0 3.5 6 37 9 86.7 4.1 6 37 10 134.0 3.2 6 37 11 77.0 4.7 6 37 12 86.1 6.4 6 37 13 88.6 4.8 6 37 14 107.1 5.9 6 38 0 143.7 5.2 6 38 1 45.1 7.5 6 38 2 157.6 3.0 6 38 3 158.6 4.0 6 38 4 240.9 5.1 6 38 5 193.2 4.8 6 38 6 156.2 4.0 6 38 7 160.1 3.5 6 38 8 88.1 3.8 6 38 9 154.9 2.9 6 38 10 69.0 4.8 6 38 11 77.7 4.7 6 38 12 98.0 5.3 6 39 0 109.1 4.5 6 39 1 83.3 6.2 6 39 2 75.7 5.0 6 39 3 173.7 7.9 6 39 4 147.4 3.8 6 39 5 94.1 4.4 6 39 6 127.1 3.8 6 39 7 94.2 4.3 6 39 8 80.9 3.5 6 39 9 43.1 6.6 6 39 10 47.4 10.4 6 40 0 102.7 4.7 6 40 1 134.2 4.6 6 40 2 87.7 6.2 6 40 3 50.4 5.3 6 40 4 104.5 3.6- 6 40 5 99.8 3.8 6 40 6 149.9 4.1 6 40 7 123.8 5.9 6 41 0 167.3 5.7 6 41 1 82.7 13.2 7 0 0 39.6 15.5 7 0 1 454.8 8.1 7 0 2 280.3 5.0 7 0 3 67.1 5.4 7 0 4 10.5 7.6 7 0 5 50.6 11.0 7 0 6 120.5 4.8 7 0 7 539.2 10.2 7 0 8 506.3 10.9 7 0 9 95.9 6.1 7 0 10 86.4 10.0 7 0 11 294.7 6.1 7 0 12 263.8 6.3 7 0 13 26.2 18.0 7 0 14 427.1 11.7 7 0 15 19.1 13.4 7 0 16 316.5 7.3 7 0 17 228.2 9.1 7 0 18 352.6 8.6 7 0 19 43.8 19.3 7 0 20 158.3 6.0 7 0 21 139.9 6.1 7 0 22 35.3 21.0 7 0 23 73.3 11.5 0 24 18.2 13.0 0 25 125.7 6.6 0 26 48.9 20.1 0 27 325.1 12.4 0 28 29.4 18.6 0 29 25.2 17.5 0 30 29.6 18.6 0 31 97.7 12.1 1 0 278.2 4.4 1 1 448.7 7.0 1 2 243.2 3.2 1 3 245.9 4.1 1 4 272.2 4.0 1 5 366.2 4.6 1 6 301.1 4.2 1 7 151.2 3.1 1 8 181.1 3.3 1 9 158.4 3.4 1 10 250.8 3.9 1 11 22.0 9.8 1 12 496.2 7.0 1 13 402.0 5.3 1 14 351.5 12.1 1 15 342.6 5.5 1 16 226.2 4.7 1 17 21.5 10.1 1 18 200.4 6.4 1 19 252.5 5.3 1 20 141.0 4.6 1 21 103.2 5.2 1 22 64.1 15.4 1 23 132.9 4.7 1 24 168.1 4.6 1 25 87.5 6.4 1 26 164.0 5.8 1 27 416.0 8.4 1 28 100.7 9.5 1 29 193.9 5.9 1 30 133.4 8.6 1 31 34.0 14.2 2 0 261.3 5.3 2 1 153.3 3.1 2 2 214.7 3.3 2 3 334.2 4.8 2 4 273.5 4.7 2 5 312.8 4.5 2 6 292.2 4.3 2 7 174.7 3.2 2 8 315.9 4.9 2 9 220.0 3.5 2 10 410.6 5.6 2 11 22.7 9.9 2 12 335.7 5.5 2 13 107.0 6.0 2 14 167.6 11.0 2 15 130.8 4.5 2 16 428.0 6.9 2 17 25.9 11.3 2 18 287.0 4.7 2 19 157.1 4.1 2 20 92.7 6.6 2 21 233.0 4.3 2 22 247.9 4.1 2 23 26.2 11.1 2 24 169.8 5.0 2 25 30.3 11.9 2 26 137.8 6.5 2 27 413.6 8.3 2 28 174.4 7.0 2 29 115.3 8.8 2 30 202.9 5.5 2 31 67.2 13.5 3 0 153.5 4.0 3 1 115.3 3.2 3 2 194.2 3.1 3 3 273.9 4.2 3 4 281.8 4.0 3 5 365.5 5.5 3 6 625.9 8.6 3 7 536.2 8.5 3 8 480.8 6.3 3 9 185.7 4.0 3 10 203.8 3.6 3 11 372.2 5.6 3 12 356.3 5.9 3 13 502.2 6.8 3 14 213 .7 6.2 3 15 333.4 5.5 3 16 406.5 6.4 3 17 218.8 4.9 3 18 188.1 5.9 3 19 270.4 4.6 3 20 91.3 6.5 3 21 91.1 5.4 3 22 64.1 11.7 3 23 79.1 6.6 3 24 106.7 6.0 3 25 142.5 6.4 3 26 118.6 6.7 3 27 299.9 12.3 3 28 22.6 11.4 3 29 176.6 6.5 3 30 120.7 7.8 3 31 88.8 9.5 4 0 335.0 4.7 4 1 451.7 8.9 4 2 366.5 4.7 4 3 339.9 4.8 4 4 248.5 4.0 4 5 61.2 4.7 4 6 439.1 5.9 4 7 369.6 5.9 4 8 279.2 4.9 4 9 98.5 4.3 4 10 113.5 3.7 4 11 390.4 5.9 4 12 198.9 7.6 4 13 468.0 6.7 4 14 247.8 6.2 4 15 226.1 4.7 4 16 560.8 8.3 4 17 178.6 6.1 4 18 68.0 8.1 4 19 150.5 4.7 4 20 75.1 7.8 4 21 349.9 5.4 4 22 154.4 5.1 4 23 70.6 7.3 4 24 19.5 9.4 4 25 130.7 5.6 4 26 94.2 8.1 4 27 257.8 14.0 4 28 38.7 16.6 4 29 250.7 5.4 4 30 173.1 6.9 4 31 33.6 15.2 5 0 407.9 6.2 5 1 224.0 3.8 5 2 245.2 3.5 5 3 268.7 3.6 5 4 258.3 3.7 5 5 165.3 3.0 5 6 488.3 6.2 5 7 274.9 4.5 PCT/GB98/02542 5 8 562.4 8.9 5 9 231.5 3. 9 5 10 194.8 3.6 5 11 265.4 4.3 5 12 271.8 5 13 387.5 8.9 5 14 282.0 4.6 5 I5 355.7 5 16 146.6 4.8 5 17 196.1 4.1 15 18 297.2 4.8 15 19 214.1 4.2 15 20 351.5 5.4 15 21 105.4 5.7 1 5 22 137.5 4.7 1 5 23 62.6 7 5 24 106.8 5.4 1 5 25 114.2 5.8 1 5 26 33.9 13.2 1 5 27 167.7 11.0 7 5 28 198.1 5.4 1 5 29 148.7 7.1 7 5 30 146.2 7.3 7 5 31 121.9 7 6 0 142.9 4.1 7 6 1 233.8 7 6 2 341.7 5.8 7 6 3 120.9 2.8 7 6 4 95.6 3.1 7 6 5 498.8 7 6 6 501.4 7 6 7 222.8 3.8 7 6 8 139.3 7 6 9 265.3 3.9 7 6 10 375.7 5.2 7 6 11 248.3 3.9 7 6 12 286.8 7 6 13 361.1 12.2 7 6 14 179.5 7 6 15 240.0 5.2 7 6 16 183.2 6.2 7 6 17 258.3 7 6 18 252.7 7 6 19 36.9 14.9 7 6 20 96.9 7.2 7 6 21 190.1 4.2 7 6 22 73.5 7 6 23 140.8 7 6 24 128.3 6.2 7 6 25 108.4 5.7 7 6 26 116.3 9.9 7 6 27 29.0 14.0 7 6 28 45.3 16.1 7 6 29 96.8 8.8 7 6 30 126.2 7 6 31 70.4 11.4 7 7 0 440.5 6.6 7 7 1 289.5 7 7 2 177.9 7 7 3 113.9 2.9 7 7 4 357.2 7 7 5 527.9 7.3 7 7 6 272.3 7 7 7 286.7 4.1 7 7 8 304.6 4.3 7 7 9 576.7 7 7 10 384.6 5.8 7 7 11 350.5 5.7 7 7 12 547.5 7.8 7 7 13 301.8 7.1 7 7 14 304.4 5.1 7 7 15 439.3 6.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/G B98/02 542 -131 1- 301.5 5.1 339.6 5.3 413.5 6.6 43.6 11.6 171.3 4.1 93.8 5.2 145.6 4.5 21.7 10.2 138.2 4.5 210.3 4.3 24.1 11.5 127.5 7.6 100.9 9.6 107.7 7.6 102.5 9.1 59.7 15.1 285.7 4.2 634.0 12.7 252.9 3.8 188.1 2.9 528.8 7.0 357.2 4.8 277.0 4.2 331.0 4.4 411.1 5.9 555.7 7.2 592.2 7.8 343.7 6.3 314.3 5.3 116.3 4.4 283.0 4.6 328.8 5.6 250.2 4.5 148.8 3.9 230.0 4.0 305.9 5.3 76.0 9.9 155.1 4.6 55.7 13.8 200.0 4.3 164.9 4.6 90.7 6.2 105.3 15.5 25.3 12.1 123.5 7.8 55.6 18.4 38.3 16.2 157.5 5.8 159.7 3.1 317.4 5.3 99.9 3.6 263.0 4.2 62.1 4.7 438.6 6.6 545.5 7.6 250.4 3.6 103.4 4.8 22.2 10.5 302.3 4.4 285.3 10.2 508.3 7.3 1 214.7 4.1 i353.7 5.7 214.6 4.2 F 240.9 4.3 24.3 11.0 27.6 11.6 194.1 4.1 1 141.1 4.5 Z 180.3 4.8 3 217.0 4.1 4 209.2 4.2 25 26 27 28 29 30 31 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 0 2 3 4 5 6 7 8 9 I I 12 1 13 1 12 1 2 1 2( 1 2 1 2 1 2~ 1 2 1 2 1 2 123 2( 21 21 170.7 326.1 1 53.2 I 178.1 214.7 202.6 50.9 1 209.6 225.0 180.7 609.6 567.0 209.6 252.1 421.0 89.3 226.6 265.5 183.3 412.5 207.6 186.7 216.7 89.4 89.0 118.6 170.4 183.4 36.5 100.8 182.1 82.4 30.7 384.7 99.9 133.3 134.5 74.3 518.2 353.8 101.2 681.1 598.5 225.0 250.7 902.1 314.6 198.7 493.0 601.1 304.5 160.9 236.8 313.0 1122.3 7 203.0 8 168.7 9 167.8 0 126.7 1 176.1 2 124.5 3 170.9 4 102.6 5 173.9 7 38.1 8 131.1 9 27.1 0 87.1 477.5 241.1 414.5 3662.6 5.3 1.5 5.3 5.3 6.4 6.9 5.1 3.1 3.9 3.5 8.3 7.9 3.1 3.5 6.3 1.6 3.9 5.7 4.8 6.1 3.9 4.3 4.1 5.5 6.3 5.6 3.9 4.7 12.0 6.0 6.0 7.6 13.0 13.4 11.3 6.3 7.1 15.3 7.0 6.2 3.0 9.5 9.0 3.8 3.8 11.5 4.7 7.0 6.7 t14.3 4.3 7.9 4.3 5.3 4.2 3.9 4.0 4.8 4.4 4.2 4.7 4.1 5.9 6.2 14.2 6.6 12.4 10.1 7.9 4.9 6.0 10.4 4 132.7 3.0 5 70.5 4.3 6 304.1 4.9 7 233.6 3.7 8 375.8 5.8 9 55.6 7.3 10 1008.3 31.7 11 416.2 5.9 12 53.7 7.4 13 189.1 3.8 14 298.7 4.6 15 81.9 6.8 16 190.8 3.8 17 264.3 4.6 18 110.2 5.5 19 98.2 6.0 20 34.5 12.3 21 21.2 9.8 22 152.3 4.9 23 259.7 4.6 24 136.4 5.0 25 153.9 6.2 26 176.8 5.0 27 236.7 4.7 28 24.9 12.2 29 104.5 8.5 30 38.2 15.1 0 635.4 10.6 1 326.0 4.8 2 419.4 6.1 3 935.3 11.5 4 369.2 6.6 5 201A 3.0 6 261.1 4.0 7 287.0 6.6 8 142.7 3.7 9 299.9 5.5 10 398.9 6.7 11 163.1 3.6 12 198.7 4.0 13 121.4 4.1 14 187.2 4.0 15 40.0 12.4 16 318.5 5.1 17 298.4 4.4 18 120.0 4.1 19 144.2 3.8 20 122.1 4.5 21 307.2 4.8 22 64.6 8.0 23 203.9 4.5 25 462.1 12.1 26 51.2 13.3 .27 31.2 13.7 28 133.0 7.0 29 145.1 6.3 30 160.3 6.2 0 397.9 6.7 1 736.4 14.6 2 184.7 3.5 3 336.2 5.5 4 787.7 11.2 5 353.4 5.1 6 244.4 5.0 7 220.9 3.9 8 237.0 5.0 1 9 312.8 12.4 1 10 349.8 5.3 1 11 586.9 11.3 1 12 609.1 8.5 1 13 364.7 5.7 t 14 168.0 4.1 158.9 3.6 178.7 4.1 449.7 7.1 225.5 3.9 280.4 4.6 80.8 6.4 263.0 5.3 182.0 4.2 155.0 17.9 55.5 20.5 213.0 25.5 11.9 28.1 12.8 135.3 7.1 113.1 550.3 8.6 154.6 2.9 329.2 420.2 6.6 624.0 10.2 481.2 6.3 267.9 6.3 131.8 17.9 357.1 5.1 509.3 6.8 158.4 5.1 381.0 5.9 145.8 3.7 136.0 3.8 263.2 4.4 232.0 4.1 124.0 5.3 106.7 4.6 155.8 5.9 I172.5 3.8 73.5 7.6 135.7 4.7 146.1 44.8 17.9 120.7 8.9 211.9 5.4 135.9 5.4 1 109.2 7.4 172.7 10.1 458.6 7.6 127.8 3.8 244.1 4.4 202.5 8.3 570.1 432.4 6.8 337.5 97.0 4.2 434.9 6.6 )341.8 6.1 1 486.9 8.4 2 354.0 5.4 3 200.6 3.7 4 87.5 6.1 5 180.2 3.9 6 425.5 6.2 7 118.3 8 69.4 6.6 9 89.1 0 136.9 4.4 1 25.6 11.2 2 108.2 4.6 3 247.5 4.6 4 316.9 9.1 5 63.6 15.1 6 99.2 7 171.3 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 -132- 28 41.1 15.3 29 24.6 12.4 0 381.5 6.3 1 217.8 5.1 2 180.9 3.6 3585.0 7.6 4 304.9 7.8 400.0 13.7 6 325.8 5.1 7 223.8 3.9 8 162.3 5.4 9 386.3 6.3 162.8 3.4 11 202.2 3.4 12 171.9 3.8 13 75.6 4.5 14 427.0 6.7 145.8 3.6 16 159.1 4.1 17 46.4 9.9 18 167.9 3.7 19 70.4 5.9 160.5 3.8 21 83.2 6.9 22 111.6 5.3 23 68.1 9.9 24 22.6 10.8 175.5 5.0 26 50.4 14.5 28 110.1 6.7 0 520.9 9.5 1 563.6 9.7 2 373.0 12.1 3 930.0 24.4 4 354.9 5.5 626.4 10.1 6 250.5 4.0 7 346.4 4.7 8 18.6 9.1 9 329.0 6.3 267.1 4.6 11 69.5 5.5 12 37.7 10.0 13 311.0 4.6 14 216.3 3 .7 89.7 4.6 16 16.3 8.0 17 143.6 3.6 18 170.2 3.6 19 133.0 3.8 65.8 9.4 21 109.2 5.5 22 127.8 5.1 23 345.4 15.2 24 99.5 6.9 135.6 5.5 26 141.0 6.3 27 26.4 12.0 28 65.3 12.5 0 105.6 5.1 1 28.6 11.1 2 391.2 7.5 3 106.0 4.6 4 194.5 3.4 444.8 7.1 6 246.4 4.3 7 32.9 8.9 8 192.4 3.6 9 534.0 7.6 149.1 4.0 11 202.0 3.5 12 112.3 6.3 I3 315.1 5.0 14 227.8 4.5 15 303.1 4.6 16 201.8 3.8 17 188.6 4.2 18 230.0 4.0 19 273.1 4.0 20 129.5 4.9 21 203.4 3.9 22 38.8 14.5 23 18.6 9.3 24 114.3 7.5 25 259.6 5.1 26 35.9 15.6 27 20.7 10.4 28 143.0 7.7 0 110.0 4.6 1 149.1 3.5 2 342.5 7.1 3 108.7 4.5 4 193.2 5.3 5 328.1 5.2 6 96.1 3.4 7 69.7 6.1 8 210.9 3.3 9 240.8 3.9 10 184.5 3.3 11 334.8 4.8 12 122.3 3.7 13 190.9 3.5 14 109.1 3.9 15 59.0 5.5 16 182.5 3.5 17 129.4 3.4 18 187.6 3.8 19 292.6 4.9 20 139.8 3.9 21 16.8 8.4 22 290.4 9.6 23 87.3 7.0 24 194.7 5.0 25 162.5 5.2 26 184.2 5.6 27 26.0 12.0 0 73.9 6.1 1 195.4 4.2 2 267.1 4.6 3 287.0 4.8 4 489.5 8.1 5 403.5 6.1 6 282.4 4.0 7 236.1 3.6 8 342.9 4.9 9 355.0 5.5 10 252.8 4.8 11 138.9 3.4 12 340.0 4.8 13 88.3 5.4 14 148.5 3.4 15 25.9 10.9 16 77.0 5.8 17 27.7 11.5 18 147.1 4.4 19 254.1 4.2 20 250.0 4.5 22 55.7 13.4 23 154.3 5.3 24 221.4 9.2 25 26.7 11.9 26 180.2 6.0 27 84.0 9.6 *0 468.7 10.3 1 142.1 3.3 2 172.6 6.1 3 283.8 4.7 4 394.2 5.7 5 350.4 5.0 6 313.2 4.8 7 258.7 4.2 8 166.3 3.3 9 323.1 4.8 10 205.5 3.3 11 76.7 3.9 12 71.6 5.3 13 202.5 4.4 14 15.5 7.7 15 110.1 3.6 16 165.5 3.4 17 147.3 4.1 18 147.0 3.8 19 122.0 4.4 20 274.5 5.5 21 172.8 23.5 22 189.9 4.4 23 72.9 7.4 24 102.6 6.5 25 112.1 7.5 26 88.9 8.6 0 93.3 2.5 1 308.6 6.6 2 133.5 4.1 3 282.1 6.2 4 28.4 11.4 5 147.1 3.6 6 198.4 3.8 7 89.0 3.7 8 19.3 8.8 9 104.4 3.2 10 188.4 3.1 11 300.4 5.2 12 194.9 3.3 13 231.6 4.7 14 166.0 3.4 15 128.5 3.7 16 72.5 6.1 17 156.9 3.7 18 100.1 5.0 19 154.7 3.9 20 168.9 16.1 21 17.1 8.4 22 15.1 7.7 23 275.8 4.5 24 180.3 4.7 25 141.4 5.1 26 70.2 13.0 0 246.5 4.2 1 242.2 4.5 2 542.4 9.5 3 388.6 7.5 4 452.8 7.7 5 371.7 6.3 6 92.9 3.4 7 154.6 3.4 8 34.4 9.1 9 89.2 3.4 10 180.0 3.1 11 112.2 3.6 12 203.4 4.0 13 154.3 3.8 14 190.1 3.6 15 229.6 3.8 16 119.7 3.5 17 179.3 3.6 18 152.7 5.1 PCT/GB98/02542 24 19 32.4 14.5 24 20 17.2 8.7 24 21 171.3 4.7 24 22 124.4 8.2 24 23 70.9 9. 1 24 24 67.4 11.1 24 25 25.1 11.7 25 0 293.8 4.6 25 1 396.4 25 2 227.4 25 3 53.1 7.2 25 4 248.0 4.1 25 5 206.6 3.3 25 6 213.5 25 7 335.2 4.9 25 8 97.8 3.2 25 9 73.9 25 10 148.0 3.3 25 11 323.7 4.6 25 12 80.0 25 13 90.6 4.3 25 14 214.0 3.4 25 15 106.4 4.1 25 16 166.5 4.1 25 17 89.5 4.9 25 18 222.9 4.7 25 19 63.5 11.9 25 20 214.1 5.4 25 21 133.1 4.2 25 22 170.8 25 23 93.9 8.3 25 24 178.2 5.2 25 25 103.6 10.5 26 0 276.7 8.6 26 1 217.4 4.4 26 2 185.2 4.1 26 3 136.7 3.6 26 4 233.1 26 5 308.0 5.1 26 6 179.8 26 7 76.7 3.3 26 8 123.7 2.9 26 9 159.1 3.4 26 10 13.7 6.7 26 11 17.4 8.3 26 12 159.7 3.2 126 13 162.1 3.3 1 26 14 252.0 4.1 1 26 15 148.7 1 26 16 114.3 4.3 1 26 17 39.7 12.7 1 26 18 316.4 13.0 7 26 19 138.9 4.9 7 26 20 61.6 8.3 7 26 21 115.3 7 26 22 92.1 7.9 7 26 23 44.6 12.2 7 26 24 28.4 13.5 7 27 0 71.5 5.1 7 27 1 176.8 3.9 7 27 2 168.8 7 27 3 203.0 4.7 7 27 4 182.5 7 27 5 159.5 3.4 7 27 6 155.0 2.7 7 27 7 282.1 4.1 7 27 8 353.3 5.3 7 27 9 94.5 4.2 7 27 10 46.2 7 27 11 28.0 10.0 7 27 12 96.3 3.8 7 27 13 189.6 3.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -133- 94.4 4.3 187.8 3.8 153.7 4.3 131.6 17.2 19.1 9.0 177.8 4.3 146.9 6.5 51.5 11.2 84.3 6.6 99.9 6.8 26.1 9.2 60.1 5.6 183.7 4.0 157.5 5.1 137.8 3.5 200.8 3.4 151.1 3.2 15.9 7.4 108.7 3.2 90.6 4.0 114.2 5.0 153.5 3.7 219.2 3.6 210.5 3.5 80.5 4.8 194.6 11.2 238.6 4.1 78.3 5.5 76.1 8.5 134.2 5.3 81.3 8.9 92.7 7.0 287.2 5.5 224.0 5.6 131.9 3.2 17.6 8.1 74.0 7.1 301.7 5.0 148.9 2.9 303.8 4.5 92.9 3.5 212.0 3.1 228.4 3.5 241.6 3.6 49.5 7.8 64.7 6.1 296.2 6.8 36.1 15.0 83.8 4.9 26.2 11.4 95.8 5.9 159.7 5.0 P227.2 5.0 113.4 5.5 97.9 6.2 248.7 4.2 194.4 3.8 232.9 5.1 299.6 5.7 268.7 5.4 237.3 4.2 131.1 2.7 142.4 3.1 70.1 4.6 222.4 3.2 55.0 5.5 1147.8 3.9 1147.4 3.6 291.9 13.5 i218.1 4.2 5176.2 4.0 7 136.3 4.0 130.9 5.6 117.3 5.7 94.3 10.0 65.2 10.6 27.5 9.3 94.1 3.6 198.0 4.6 199.9 3.7 273.5 5.2 232.3 5.0 66.4 4.1 106.4 3.2 265.6 4.1 120.4 3.1 108.3 3.9 84.9 7.4 187.3 11.7 294.8 5.0 159.1 3.9 200.5 3.8 30.8 11.0 139.6 5.5 162.2 4.2 126.9 4.5 87.5 6.9 223.1 4.8 108.4 3.6 154.1 3.6 35.8 9.8 156.9 3.7 124.7 3.7 39.4 9.3 149.8 3.7 142.4 3.0 121.1 .4.6 P185.9 10.2 147.4 3.7 98.0 4.5 108.1 4.0 84.1 4.7 p72.9 6.7 164.6 3.8 196.8 3.9 66.2 7.4 P102.3 7.2 35.1 8.1 91.8 5.8 187.1 4.0 210.0 4.7 93.0 4.5 231.3 5.5 66.2 5.0 145.2 8.2 213.6 9.0 116.3 4.2 1 25.4 10.1 Z 140.7 4.4 389.5 4.3 t 95.7 4.6 5 77.9 6.5 5 163.8 3.9 7 147.2 5.3 9 162.7 4.8 173.5 4.4 64.8 6.3 314.1 6.1 59.5 14.0 1323.7 16.6 275.9 8.7 159.5 3.7 73.8 4.5 1244.7 3.9 9 210.7 3.8 10 62.4 5.4 11 145.5 3.5 12 202.7 4.0 13 129.9 3.7 14 121.7 3.8 15 173.1 3.7 16 77.9 6.4 17 74.2 8.0 0 100.6 6.1 3 71.8 7.7 4 177.0 4.1 5 17.2 8.0 6 33.4 10.3 7 224.1 3.8 8 121.3 3.6 9 90.8 4.8 10 166.1 3.4 11 123.8 3.6 12 166.4 3.4 13 171.3 3.8 14 144.1 4.6 15 52.9 11.0 0 65.9 5.2 1 151.6 4.1 2 195.3 4.5 3 25.7 9.8 4 68.3 6.7 5 116.6 4.1 6 238.1 5.5 7 207.4 4.4 8 118.4 3.4 9 87.1 4.5 10 87.6 4.6 11 171.4 3.4 12 185.5 3.6 13 70.0 6.7 14 103.7 5.2 0 275.2 6.4 1 155.7 3.3 2 64.9 5.2 3 107.8 4.1 4 184.5 4.4 5 186.6 4.1 6 106.5 6.5 7 83.8 4.0 8 134.2 4.8 9 123.9 3.1 10 108.5 3.8 11 106.8 3.9 12 43.0 10.7 0 246.9 5.1 1 62.8 5.1 2 177.6 4.3 3 38.3 9.4 4 276.9 5.4 5 60.2 6.4 6 88.5 4.8 7 83.8 5.3 8 198.9 3.6 9 23.4 9.0 10 41.1 9.9 0 40.0 7.7 1 186.0 4.0 2 129.5 3.5 3 93.6 3.8 4 174.6 3.9 I5 44.1 9.0 6 71.2 5.3 7 177.9 4.1 8 78.8 7.3 I0 82.0 3.5 94.8 3.7 56.2 5.8 51.7 6.6 94.0 4.3 7.8 5.8 641.2 14.5 80.8 5.1 94.4 299.5 6.2 459.2 8.2 349.9 8.1 13.3 953.9 19.7 145.6 5.7 19.2 12.7 204.5 14.7 194.3 6.4 90.0 10.4 730.4 16.6 210.3 63.5 23.6 378.4 7.2 136.5 6.9 45.4 22.3 238.4 6.3 14.9 10.7 34.2 21.5 73.0 13.4 151.9 10.6 83.2 12.1 316.0 303.1 12.4 65.6 21.4 22.2 15.8 87.7 2.6 296.0 4.6 50.4 5.2 235.9 3.8 293.8 4.1 91.8 4.2 598.8 642.7 9.7 258.8 4.4 372.4 5.6 1294.7 4.4 766.5 10.7 127.4 7.8 1422.7 397.3 6.3 i84.0 8.2 413.4 6.2 107.4 1 89.2 7.6 )121.0 6.4 )109.0 6.2 136.3 13.7 1196.4 4.6 156.4 4.4 t 44.0 14.1 5 47.3 13.4 5 31.1 15.3 7 73.8 9.6 3 185.7 5.9 S164.0 6.9 3110.5 1 72.2 13.8 I34.0 6.6 175.2 340.4 546.8 1 307.6 ;122.9 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -134- 2 6 37.3 12.5 2 7 223.4 3.7 2 8 339.7 5.1 2 9 131.8 4.0 2 10 265.6 4.0 2 11 381.9 6.8 2 12 246.1 9.-3 2 13 374.3 5.6 2 14 290.0 5.1 2 15 109.6 5.4 2 16 213.0 4.7 2 17 123.0 5.1 2 18 224.1 4.2 2 19 256.8 4.7 2 20 98.9 5.9 2 21 155.4 5.1 2 22 203.7 4.6 2 23 66.8 8.3 2 24 150.0 5.0 2 25 34.0 13.0 2 26 153.0 11.6 2 27 144.4 5.0 2 28 177.6 5.4 2 29 147.3 9.2 2 30 100.5 10.7 2 31 22.6 11.3 3 0 397.5 6.3 3 1 217.3 3.8 3 2 357.5 5.3 3 3 109.9 3.6 3 4 151.9 3.0 3 5 49.9 6.0 3 6 283.6 4.1 3 7 81.3 4.8 3 8 421.3 6.1 3 9 283.4 4.9 3 10 191.0 4.9 3 11 158.7 5.6 3 12 559.6 18.3 3 13 179.7 4.2 3 14 200.6 4.7 3 15 395.2 5.7 3 16 221.9 4.2 3 17 172.3 4.2 3 18 310.7 4.8 3 19 223.9 5.2 3 20 274.9 4.5 3 21 100.9 6.2 3 22 134.4 4.6 3 23 169.1 4.2 3 24 128.0 5.6 -3 25 27.4 12.1 3 26 270.2 18.8 3 27 104.8 6.6 3 28 226.2 5.3 3 29 248.0 6.1 3 30 59.7 15.1 3 31 160.9 7.5 4 0 453.1 6.0 4 1 83.0 3.9 4 2 506.0 7.0 4 3 254.7 4.1 4 4 73.7 4.3 4 5 222.7 3.7 4 6 146.5 3.3 4 7 91.7 5.6 4 8 554.7 8.4 4 9 510.5 8.0 4 10 512.6 7.4 4 11 238.1 4.1 4 12 748.3 19.7 4 13 225.7 4.2 4 14 149.7 5.8 4 15 325.0 5.5 4 16 259.5 4.3 4 17 211.4 4.0 4 18 162.2 4.7 4 19 48.4 12.9 4 20 56.8 10.2 4 21 181.3 4.1 4 22 233.5 4.9 4 23 83.6 8.2 4 24 176.8 4.8 4 25 31.0 13.2 4 26 248.4 11.2 4 27 67.6 10.5 4 28 148.9 7.1 4 29 134.3 8.4 4 30 192.9 6.0 5 0 297.6 4.4 5 1 109.0 3.2 5 2 331.0 4.8 5 3 290.3 4.4 5 4 223.3 3.5 5 5 264.0 4.1 5 6 518.7 7.8 5 7 622.2 10.6 5 8 30.2 9.4 5 9 402.3 6.6 5 10 587.9 10.6 5 11 119.3 4.2 5 12 342.7 19.5 5 13 36.8 13.6 5 14 372.6 5.9 5 15 123.9 6.7 5 16 408.8 5.7 5 17 236.4 4.2 5 18 216.6 4.6 5 19 233.0 4.4 5 20 107.5 5.4 5 21 82.4 6.8 5 22 63.4 8.9 5 23 19.4 9.4 5 24 186.7 4.2 5 25 154.9 6.4 5 26 409.3 11.9 5 27 89.2 9.1 5 28 139.1 9.6 5 29 68.5 13.7 5 30 31.5 14.0 6 0 26.0 7.9 6 1 588.4 11.4 6 2 140.2 2.8 6 3 207.5 3.2 6 4 43.9 9.3 6 5 56.9 8.3 6 6 678.8 9.4 6 7 305.3 5.0 6 8 185.9 3.9 6 9 264.0 4.5 6 10 675.3 9.8 6 11 37.9 14.5 6 12 115.7 10.4 6 13 352.0 5.2 6 14 304.9 5.3 6 15 96.1 9.2 6 16 354.0 5.1 6 17 79.8 9.7 16 18 65.5 7.6 6 19 161.4 4.1 6 20 157.1 4.3 16 21 237.9 4.2 16 22 66.0 9.0 16 23 71.5 8.3 6 24 97.6 6.1 6 25 163.9 4.9 6 26 277.0 13.2 6 27 184.7 6.1 6 28 164.4 7.3 6 29 70.7 16.1 6 30 182.1 8.2 7 0 452.1 7.6 7 1 341.6 6.2 7 2 385.7 5.6 7 3 305.8 4.2 7 4 335.4 4.8 7 5 363.3 5.2 7 6 525.6 8.2 7 7 299.2 4.7 7 8 430.7 7.1 7 9 185.9 4.6 7 10 345.8 5.4 7 11 407.5 14.7 7 12 499.9 6.9 7 13 190.8 4.2 7 14 155.8 4.5 7 15 260.9 4.9 7 16 96.5 5.7 7 17 274.9 4.3 7 18 303 .1 4.5 7 19 243.7 4.1 7 20 105.0 7.2 7 21 18.7 9.5 7 22 143.6 4.7 7 23 68.2 8.0 7 24 45.6 14.2 7 25- 94.2 7.2 7 26 85.7 20.9 7 27 91.5 8.6 7 28 103.2 9.3 7 29 77.5 17.8 7 30 173.3 6.2 8 0 757.9 12.7 8 1 382.8 6.4 8 2 646.4 9.7 8 3 462.2 7.0 8 4 234.7 3.8 8 5 364.7 5.2 8 6 228.2 3.4 8 7 245.5 4.0 8 8 103.5 6.2 8 9 409.8 6.1 8 10 464.5 6.5 8 11 416.2 16.7 8 12 178.5 4.1 8 13 168.9 5.2 8 14 182.9 4.1 8 15 344.9 5.5 8 16 123.8 4.6 8 17 205.7 4.6 8 18 230.3 4.4 8 19 79.8 6.2 8 20 167.4 4.6 8 21 148.0 4.4 8 22 130.2 4.8 8 23 127.6 4.9 8 24 184.2 4.8 8 26 29.6 13.9 8 27 49.6 14.5 8 28 101.5 9.8 8 29 105.2 8.7 8 30 32.8 14.2 9 0 494.8 8.6 9 1 210.1 3.9 9 2 313.2 4.5 9 3 252.4 3.8 PCT/GB98/02542 9 4 609.2 10.2 9 5 36.6 10.9 9 6 102.0 3.7 9 7 168.8 3.4 9 8 128.9 7.1 9 9 503.9 9 11 180.2 4.3 9 12 197.0 5.9 9 13 226.8 4.4 9 14 214.9 4.1 9 15 90.0 7.3 9 16 164.1 9 17 510.2 9 18 53.9 8.2 9 19 126.7 4.4 9 20 69.7 8.3 9 21 43.0 11.3 9 22 173.0 9 23 114.8 5.6 9 24 142.3 4.8 9 25 70.7 26.1 9 26 151.0 6.2 9 27 102.5 6.9 9 28 76.1 10.3 9 29 63.6 16.8 9 30 188.9 10 0 430.6 6.8 10 1 337.3 5.9 10 2 186.5 3.2 10 3 193.3 10 4 17.4 8.1 10 5 377.3 10 6 166.7 3.1 10 7 234.2 4.1 10 8 382.6 6.4 110 9 335.7 5.2 110 10 305.1 17.5 110 11 631.4 8.7 10 12 88.6 6.4 110 13 91.6 5.7 110 14 247.3 3.9 110 15 272.2 5.1 110 16 248.1 4.3 110 17 130.6 110 18 238.4 4.1 10 19 50.5 9.6 10 20 102.3 4.9 3 10 21' 33.8 11.6 3 10 22 53.3 10.9 3 10 23 94.5 3 10 24 26.2 11.6 3 10 25 397.4 13.7 3 10 26 97.4 3 10 27 22.8 11.3 9 10 28 105.0 8.8 B 10 29 33.1 15.1 9 10 30 53.6 19.0 8 11 0 451.3 6.3 8 11 1 316.6 5.1 8 11 2 560.8 9.6 8 11 3 754.3 9.9 8 11 4 312.4 4.3 8 11 5 116.6 4.4 8 11 6 468.2 8 11 7 537.6 10.6 8 11 8 54.6 8.8 8 11 9 352.3 9.6 8 11 10 325.0 4.8 8 11 11 426.7 7.3 8 11 12 307.0 4.9 8 11 13 111.0 4.6 8 11 14 220.8 4.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PTG9/24 PCT/GB98/02542 -13 322.6 5.1 158.8 3.9 217.0 5.4 119.3 4.7 81.2 5.9 116.4 5.1 137.6 5.0 107.6 7.4 94.4 7.0 21.2 10.2 182.5 16.2 104.3 6.4 202.8 5.9 110.1 8.6 172.8 6.3 268.4 4.0 346.1 5.8 379.5 7.1 168.5 3.2 289.6 5.5 269.2 4.8 *294.1 6.3 25.2 11.5 23.1 11.0 521.3 7.9 49.1 10.9 69.7 7.1 112.2 4.6 246.8 5.1 339.9 5.1 190.0 4.1 218.0 3.9 137.9 4.6 193.2 3.8 102.6 4.9 268.8 4.5 *122.5 6.2 303.6 4.8 90.7 8.0 *110.8 7.9 34.4 15.7 238.3 5.2 1111.2 8.7 128.8 6.5 229.0 3.8 17.2 7.6 168.8 3.0 897.6 12.4 336.8 6.3 544.3 7.8 212.8 3.9 578.0 18.5 388.3 6.2 776.7 15.8 )329.1 6.6 1 155.9 4.4 2 230.1 4.9 3 435.2 6.3 4 289.4 4.7 150.9 4.7 6 414.4 6.0 7 81.3 6.6 8 141.5 3.9 9 257.7 4.2 0 58.0 9.4 1 248.3 4.4 2 111.0 7.4 3 129.4 5. 1 4 248.5 12.7 98.3 8.0 6 73.0 10.5 7 61.7 14.3 '3 13 14 '4 14 14 14 '4 '4 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 15 is 15 15 15 15 15 15 15 15 15 115 15 9 15 8 1 I 1 8 28 41.1 14 29 81.6 1 0 328.6 5 1 308.8 5 2 660.6 1 3 259.6 5 4 79.8 4.

5 504.0 8 7 184.0 4 8 17 .7 8 9 148.4 5 10 283.6 11 306.9 12 425.2 13 292.7 14 198.0 15 314.3 16 208.1 17 141.6 18 32.5 1 19 112.1 20 17.6 21 161.0 22 67.3 1 23 115.2 24 175.3 25 147.9 26 86.0 27 130.1 28 113.4 29 78.5 1 0 471.2 1 500.2 2 183.8 3 265.6 4 310.4 1 5 290.1 1 6 840.5 1 7 240.2 8 250.1 9 476.2 10 302.7 11 16.9 12 69.0 13 221.0 14 254.7 15 214.3 16 154.5 17 119.2 18 147.0 19 81.4 20 77.5 21 90.7 22 158.6 23 139.2 24 21.5 525 156.1 5 26 168.4 5 27 159.8 5 28 149.9 6 0 406.3 6 1 171.5 6 4 313.1 6 5 293.6 6 6 46.4 6 7 363.4 6 8 307.4 6 9 328.4 6 10 206.9 6 11 292.6 6 12 89.0 6 13 260.8 5.7 1.0 .9 .5 1.7 .9 .4 3 .3 .5 3 4.9 5.4 6.9 4.8 3.9 5.0 4.8 4.5 2.3 4.6 3.8 5.1 0.1 6.0 11.4 5.3 8.4 8.5 1.7 7.7 8.1 4.7 4.0 2.6 3.0 2.6 3.9 4.0 7.0 5.0 8.4 6.1 3.8 4.4 3.7 4.7 3.8 4.0 6.5 5.9 6.5 4.9 5.3 10.4 5.9 6.5 6.8 6.5 8.8 10.8 5.2 4.2 9.2 5.0 5.2 5.3 4.1 4.5 5.7 4.6 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 24 25 06 27 14 3 8 8 2 8 2 8 2 8 2 8 2 8 2 942 9 299.7 84.25 192.4 107.5 56.18 227.1 130.3 227.0 88.5 395.5 114.9 100.2 70.9 1 218.8 128.9 362.6 333.3 119.7 259.7 189.5 131.6 17.9 8 186.6 170.4 151.9 38.7 1 355.7 84.5 167.8 95.8 244.6 296.4 269.7 16.9 69.5 I193.6 53.3 75.1 69.4 118.4 24.1 53.9 279.3 275.0 247.6 292.7 332.1 190.1 135.3 248.3 228.5 207.5 0 141.1 1 168.1 2 130.0 3 191.6 4 189.4 5 100.1 6 69.8 7 152.9 8 24.0 9 188.2 0 215.3 1 144.7 2 284.6 3 95.0 .4 165.0 .5 202.9 :6 26.6 7 208.1 01 422.8 1 346.6 4.6 3.7 5.2 1.1 4.1 4.0 4.4 16.9 6.3 7.5 0.1 5.5 6.6 5.5 4.5 4.3 3.8 3.5 .3 3.4 3.5 3.8 1.7 5.7 5.3 3.6 5.0 3.8 4.5 4.5 8.3 8.6 4.3 13.9 9.1 11.3 8.3 11.8 16.0 4.3 4.8 6.2 4.9 4.8 3.4 3.5 4.0 3.8 3.7 3.4 3.6 3.6 3.7 3.7 4.1 6.6 3.9 10.4 4.1 4.2 5.4 21.9 6.4 5.2 4.8 12.4 5.9 8.9 5.6 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24 25 06 27 3 4 5 6 7 8 9 1 1: 1: 1: 14 1~ 1: 2 2 2 '2 2 2 2 2 24 2~ 21.2 8 446.3 538.6 331.5 233.3 298.0 291.8 251.0 230.3 221.1 207.3 256.1 152.2 355.2 320.8 111.6 119.4 90.7 I139.6 56.4 1 231.6 163.3 80.1 164.8 96.1 389.2 122.4 146.0 183.6 446.9 325.6 60.8 26 1.3 386.9 173.7 )15.5 1 328.2 Z 121.9 3 88.5 4 48.5 5 63.4 6 78.5 7 77.8 8 80.6 9 85.5 0 209.4 1 328.0 2 87.6 3 160.6 4 172.7 5 318.9 6 119.3 383.8 1 264.3 2386.5 3 297.3 4 121.5 5 267.6 6 188.2 7 47.0 8 112.8 9 68.7 0 392.2 1 229.9 ,2 286.8 13 54.5 14 143.9 [5 213.9 16 94.2 17 79.5 18 33.9 19 66.8 .2 6.7 4.7 3.7 4.4 4.1 3.6 4.3 3.6 4.2 3.4 4.7- 6.7 4.3 .0.6 4.8 9.1 8.9 6.8 7.1 7.4 4.7 3.3 3.6 7.4 4.8 5.8 6.7 3.3 7.7 5.7 4.8 12.0 5.9 6.6 6.4 4.1 18.0 6.8 5.7 4.8 5.4 6.1 5.7 6.2 6.3 4.3 5.7 6.9 4.1 6.3 3.8 3.6 5.6 5.3 11.4 7.1 SUBSTITE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -136- 8 21 21 14.6 7.4 8 24 14 150.5 3.4 8 27 12 151.1 3.8 8 30 18 130.3 8 21 22 44.4 12.3 8 24 15 158.7 3.5 8 27 13 53.8 8.4 8 30 19 58.6 9.6 8 21 23 163.2 5.5 8 24 16 72.9 6.6 8 27 14 88.2 5.5 8 30 20 159.5 5.6 8 21 24 141.0 6.6 8 2417 164.8 3.7 8 27 16276.0 6.4 8 31 0 17.1 8.2 8 21 25 113.9 11.9 8 24 18 149.0 11.4 8 27 17 120.6 3.9 8 31 1 169.1 8 21 26 124.2 7.7 8 24 19 175.4 4.2 8 27 18 25.6 11.0 8 31 2 167.3 4.2 8 22 0 258.1 5.4 8 24 20 157.2 5.2 8 27 19 165.0 4.5 8 31 3 204.2 4.7 8 22 1 132.6 2.8 8 24 21 106.7 5.7 8 27 20 115.6 5.2 8 31 4 105.5 4.2 8 22 2 157.4 4.9 8 24 22 125.8 5.2 8 27 21 90.1 7.2 8 31 5 90.7 4.8 8 22 3 103.5 5.0 8 24 23 118.8 7.4 8 27 22 67.1 11.1 8 31 6 154.9 3.4 8 22 4 199.4 3.3 8 24 24 98.1 6.9 8 28 0 318.1 5.4 8 31 7 154.5 3.2 8 22 5 90.1 3.7 8 25 0 153 .1 3.2 8 28 1 48.4 7.6 8 31 8 36.6 8.7 8 22 6 334.5 5.1 8 25 1 179 .4 3.7 8 28 2 320.7 6.4 8 31 9 65.5 8 22 7 71.2 5.1 8 25 2 184 .2 4.6 8 28 3 13.8 6.9 8 31 10 238.7 8.7 8 22 8 373.0 5.2 8 25 3 198.2 4.7 8 28 4 92.4 3.2 8 31 11 89.1 4.9 8 22 9 49.0 7.0 8 25 4 198.2 3.6 8 28 5 112.0 4.4 8 31 12 48.2 9.9 8 22 10 221.7 4.3 8 25 5 272 .0 3.9 8 28 6 126.7 3.1 8 31 13 196.2 3.7 8 22 11 111.0 4.9 8 25 6 30.1 9.0 8 28 7 48.9 7.8 8 31 14 118.4 4.6 8 22 12 357.1 4.6 8 25 7 228.8 3.6 8 28 8 156.6 3.3 8 31 15 104.1 8 22 13 403.5 5.7 8 25 8 35.1 9.8 8 28 9 139.4 3.1 8 31 16 119.3 8 22 14 153.1 3.9 8 25 9 16.7 8.0 8 28 10 33.8 10.3 8 31 17 71.5 8 22 15 149.5 3.5 8 25 10 89.4 4.0 8 28 11 230.5 3.9 8 31 18 140.9 4.7 8 22 16 62.8 6.8 8 25 11 132.0 3.5 8 28 12 111.8 4.6 8 31 19 17.8 8.8 8 22 17 105.7 6.1 8 25 12 101.7 4.1 8 28 13 114.2 4.3 8 32 0 151.0 3.8 8 22 18 78.4 6.5 8 25 13 217.8 3.7 8 28 14 338.9 13.8 8 32 1 94.0 4.2 8 22 19 113.7 6.7 8 25 14 74.5 5.2 8 28 15 160.0 4.9 8 32 2 67.8 5.8- 8 22 20 265.5 7.8 8 25 15 32.1 11.2 8 28 16 133.6 4.7 8 32 3 187.0 3.7 8 22 21 71.4 8.1 8 25 16 102.9 4.8 8 28 17 148.1 4.7 8 32 4 105.2 4.8 8 22 22 171.7 4.3 8 25 17 70.4 19.9 8 28 18 53.5 8.6 8 32 5 87.7 4.8 8 22 23 104.8 5.7 8 25 18 115.8 4.9 8 28 19 143.9 7.1 8 32 6 136.3 3.6 8 22 24 21.5 10.7 8 25 19 28.6 11.3 8 28 20 26.5 11.3 8 32 7 205.5 6.6 8 22 25 138.9' 5.9 8 25 20 92.6 7.8 8 28 21 154.4 6.6 8 32 8 274.7 12.5 8 23 0 515.4 9.0 8 25 21 136.9 4.6 8 28 22 91.9 20.0 8 32 9 267.1 4.6 8 23 1 20.8 8.6 8 25 22 87.0 8.6 8 29 0 134.3 2.9 8 32 10 30.2 10.5 8 23 2 431.7 7.2 8 25 23 78.2 10.2 8 29 1 86.7 4.8 8 32 11 290.4 4.6 8 23 3 212.5 3.9 8 25 24 134.8 7.3 8 29 2 162.4 3.1 8 32 12 112.8 8 23 4 220.6 3.8 8 26 0 224.9 4.9 8 29 3 69.5 8.8 8 32 13 171.6 3.8 8 23 5 174.9 2.9 8 26 1 300.3 5.9 8 29 4 166.3 3.2 8 32 14 122.1 8 23 6 182.3 3.0 8 26 2 374.4 7.4 8 29 5 88.8 3.8 8 32 15 178.5 3.9 8 23 7 218.3 3.4 8 26 3 205.3 4.6 8 29 6 116.4 3.4 8 32 16 110.4 4.6 8 23 8 84.8 4.9 8 26 4 41.7 13.0 8 29 7 132.7 3.2 8 32 17 84.1 5.4 8 23 9 74.4 4.6 8 26 5 348.2 5.0 8 29 8 146.9 3.0 8 33 0 61.3 6.7 8 23 10 133.6 3.1 8 26 6 52.8 5.5 8 29 9 196.6 3.4 8 33 1 144.7 4.6 8 23 11 471.1 7.2 8 26 7 88.4 3.9 8 29 10282.0 4.4 8 33 2 83.1 5.7 8 23 12 354.7 5.4 8 26 8 66.6 4.3 8 29 11 87.9 4.4 8 33 3 163.2 8 23 13 133.0 3.7 8 26 9 224.9 3.7 8 29 12 166.8 3.8 8 33 4 93.9 12.3 8 23 14 15.4 7.5 8 26 10 35.7 7.7 8 29 13 310.8 8.9 8 33 5 239.6 7.7 8 23 15 115.1 4.9 8 26 11 32.4 10.6 8 29 15 223.8 3.9 8 33 7 63.2 6.1 8 23 16 97.4 4.9 8 26 12 26.3 10.0 8 29 16 33.8 11.9 8 33 8 120.3 3.8 8 23 17 20.9 9.5 8 26 13 24.0 10.1 8 29 17 87.3 7.6 8 33 9 86.7 4.2 8 23 18 176.1 3.8 8 26 14 304.6 4.2 8 29 18 148.7 4.0 8 33 10 163.3 3.6 8 2.3 19 365.9 17.3 8 26 15 215.7 3.9 8 29 19 138.5 4.8 8 33 11 85.7 8 23 20 96.4 7.0 8 26 16 111.6 9.2 8 29 20 169.4 4.3 8 33 12 49.4 8 23 21 183.1 4.9 8 26 17 50.5 16.2 8 29 21 71.2 9.3 8 33 13 164.0 4.8 8 23 22 139.5 5.2 8 26 18 105.9 5.4 8 30 0 86.8 4.6 8 33 14 182.6 8 23 23 235.9 5.3 8 26 19 109.4 6.5 8 30 1 119.8 3.8 8 33 15 157.5 4.3 8 23 24 230.7 6.0 8 26 20 85.2 6.8 8 30 2 96.5 4.2 8 33 16 86.8 5.9 8 23 25 68.5 9.9 8 26 21 84.6 8.1 8 30 3 151.1 3.8 8 33 17 64.0 9.2 8 24 0 551.5 11.1 8 26 22 16.0 8.0 8 30 4 227.9 5.0 8 34 0 83.7 9.2 8 24 1 301.8 4.7 8 26 23 30.3 12.2 8 30 5 115.9 3.9 8 34 2 137.5 4.7 8 24 2 550.7 10.9 8 27 0 182.2 3.3 8 30 6 154.8 3.1 8 34 4 126.4 4.1 8 24 3 123.1 6.4 8 27 1 132.4 4.0 8 30 7 236.2 3.6 8 34 5 66.4 5.9 8 24 4 268.2 4.3 8 27 2 94.6 4.5 8 30 8 75.6 4.4 8 34 6 181.3 4.4 8 24 5 96.3 3.4 8 27 3 236.5 4.5 8 30 9 116.0 3.1 8 34 7 250.5 8 24 6 11.4 5.7 8 27 4 244.2 5.4 8 30 10 140.9 3.6 8 34 8 106.9 3.6 8 24 7 161.7 3.1 8 27 5 273.9 6.1 8 30 11 22.6 11.1 8 34 9 104.6 8 24 8 224.2 3.7 8 27 6 193.1 3.9 8 3012 141.9 16.4 8 34 10 61.3 6.1 8 24 9 298.7 4.8 8 27 7 126.4 3.1 8 30 13 122.1 4.5 8 34 11 236.4 8 24 10 171.9 3.2 8 27 8 99.7 3.6 8 30 14 113.6 4.8 8 34 12 124.8 3.9 8 24 11 281.2 4.6 8 27 9 139.5 3.3 8 30 15 112.6 5.8 8 34 13 181.3 8 24 12 174.8 3.4 8 27 10 146.1 3.3 8 30 16 194.0 3.9 8 34 14 77.8 6.6 8 24 13 107.0 4.0 8 27 11 177.5 4.1 8 30 17 85.8 5.9 8 34 15 22.2 10.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -137- 8 35 0 80.6 5.5 8 35 1 108.0 4.1 8 35 2 99.7 3.9 8 35 3 135.5 3.7 8 35 4 113.1 4.1 8 35 5 125.5 5.0 8 35 6 127.7 4.5 8 35 7 235.1 4.3 8 35 8 124.3 3.5 8 35 9 173.5 3.4 8 35 10 57.0 6.9 8 35 11 118.5 4.1 8 35 12 67.8 7.3 8 35 13 50.2 7.3 8 35 14 89.8 6.8 8 36 0 50.1 8.1 8 36 1 101.1 3.8 8 36 2 84.8 4.2 8 36 3 91.4 4.4 8 36 4 14.7 7.2 8 36 5 120.5 4.4 8 36 6 124.2 4.1 8 36 7 210.8 4.1 8 36 8 254.7 4.9 8 36 9 122.0 3.6 8 36 10 55.5 6.9 8 36 11 102.9 4.5 8 36 12 54.3 7.2 8 36 13 64.6 13.9 8 37 0 102.3 4.3 8 37 1 204.2 5.1 8 37 2 91.8 4.4 8 37 3 32.4 9.9 8 37 4 69.9 6.6 8 37 5 65.7 6.5 8 37 6 199.3 4.6 8 37 7 14.4 7.2 8 37 8 102.2 5.7 8 37 9 118.4 3.8 8 37 10 129.2 3.6 8 37 11 121.6 4.2 8 38 0 118.5 3.7 8 38 1 137.7 3.6 8 38 2 133.6 3.5 8 38 3 100.0 4.5 8 38 4 78.1 5.5 8 38 5 49.8 9.1 8 38 6 26.0 11.2 8 38 7 148.9 4.5 8 38 8 71.9 6.8 8 39 0 204.9 8.3 8 39 1 132.2 4.2 8 39 2 67.0 5.4 8 39 3 24.7 10.0 8 39 4 69.1 5.8 8 39 5 71.4 5.8 8 39 6 106.3 5.3 9 0 0 680.5 18.8 9 0 1 81.9 20.8 9 0 2 321.0 6.6 9 0 3 12.2 8.9 9 0 4 155.7 11.1 9 0 5 165.6 5.4 9 0 6 291.6 6.5 9 0 7 290.8 8.9 9 0 8 48.6 24.0 9 0 9 452.8 9.9 9 0 10 274.7 11.5 9 0 12 184.4 6.5 9 0 13 602.5 13.7 9 0 14 183.2 6.7 9 0 15 178.9 5.7 0 16 129.8 6.5 0 17 291.8 7.9 0 18 193.7 5.8 0 19 13.5 10.0 0 20 25.3 15.3 0 21 52.4 16.0 0 22 92.8 8.8 0 23 71.9 16.0 0 24 57.1 18.9 0 25 15.0 11.2 0 26 31.6 21.2 0 27 150.7 8.0 0 28 39.9 22.4 0 29 302.6 8.8 0 30 30.9 20.6 1 0 883.2 15.4 1 1 546.5 9.6 1 2 334.8 5.0 1 3 161.7 3.6 1 4 508.6 7.4 1 5 586.3 8.6 1 6 229.7 4.0 1 7 231.4 3.9 1 8 558.5 8.5 1 9 356.7 6.7 1 10 315.8 9.4 1 11 103.2 18.5 1 12 411.6 6.2 1 13 252.6 5.1 1 14 70.7 9.2 1 15 274.1 5.0 1 16 19.8 9.8 1 17 190.3 4.3 1 18 212.0 7.3 1 19 63.7 8.7 1 20 160.2 4.1 1 21 112.2 5.2 1 22 72.8 7.9 1 23 48.9 13.9- 1 24 20.8 10.3 1 26 95.2 10.4 1 27 243.5 5.4 1 28 177.9 6.1 1 29 90.2 10.4 1 30 144.5 7.6 2 0 179.0 3.4 2 1 575.3 9.3 2 2 185.6 3.7 2 3 241.5 4.0 2 4 520.7 7.6 2 5 424.9 6.3 2 6 182.6 3.7 2 7 186.5 3.6 2 8 497.1 7.4 2 9 500.9 7.8 2 10 337.0 11.0 2 11 211.7 6.1 2 12 270.7 4.4 2 13 335.2 5.8 2 14 252.1 4.5 2 15 148.3 5.2 2 16 322.2 5.4 2 17 64.6 8.0 2 18 59.3 8.5 2 19 108.9 5.4 I2 20 64.1 8.4 2 21 27.9 11.9 I2 22 128.5 4.6 I2 23 170.3 4.4 I2 24 60.2 9.9 2 25 39.3 16.5 02 26 30.5 14.0 2 27 117.6 6.5 2 28 53.2 16.1 2 29 120.2 7.1 2 30 200.2 5.8 3 0 250 .3 3.9 3 1 217 .9 4.6 3 2 373.1 5.7 3 3 269.3 4.2 3 4 115.9 5.0 3 5 79.2 4.9 3 6 13.0 6.6 3 7 64.0 7.8 3 8 238.4 4.9 3 9 382.5 6.1 3 11 24.9 11.9 3 12 667.6 9.4 3 13 417.5 7.0 3 14 283.2 4.5 3 15 313.5 5.6 3 16 106.9 6.0 3 17 214.0 4.8 3 18 122.7 4.6 3 19 116.8 5.2 3 20 131.4 5.0 3 21 86.9 6.3 3 22 152.9 4.9 3 23 54.0 14.0 3 24 104.3 6.0 3 25 195.9 13.6 3 26 32.9 14.8 3 27 196.3 5.0 3 28 89.9 9.9 3 29 175.3 6.6 3 30 85.8 11.2 4 0 67.4 4.6 4 1 356.1 6.2 4 2 320.2 4.5 4 3 629.3 8.7 4 4 246.9 4.4 4 5 238.8- 3.9- 4 6 42.9 9.1 4 7 741.0 9.5 4 8 379.8 18.4 4 9 18.0 8.9 4 10 386.8 13.2 4 11 91.3 6.1 4 12 315.8 4.8 4 13 26.9 11.7 4 14 257.5 4.4 4 15 139.1 5.0 4 16 114.1 7.0 4 17 309.7 5.0 4 18 76.3 6.8 4 19 167.6 3.7 4 20 109.9 5.3 P4 21 120.4 5.5 4 22 191.5 4.5 I4 23 153.5 4.7 I4 24 214.7 4.6 I4 25 206.4 15.6 4 26 66.6 12.9 4 27 154.0 6.7 4 28 111.9 8.8 4 29 155.5 6.0 4 30 30.0 14.6 5 0 276.2 4.1 5 1 388.8 6.3 )5 2 286.9 4.2 )5 3 370.4 5.7 S5 4 70.8 5.0 )5 5 388.9 7.3 S5 6 508.0 7.6 PCT/GB98/02S42 5 7 654.9 8.9 I5 8 252.8 13.1 5 9 164.4 5 10 534.8 20.5 I5 11 286.7 4.6 5 12 69.2 10.5 I5 13 225.8 4.3 I5 14 221.0 5 15 312.5 4.7 5 16 104.9 5.7 I5 17 94.6 6.2 5 18 136.4 5.6 5 19 99.2 5 20 102.0 6.3 5 21 86.3 6.6 5 22 142.6 5.7 5 23 90.3 6.2 5 24 60.9 11.4 5 25 345.8 11.3 5 26 144.3 7.4 5 27 93.7 12.1 )5 28 174.4 )5 29 22.9 11.4 )6 0 378.3 5.6 )6 1 252.6 3.6 )6 2 265.9 4.2 )6 3 208.3 3.3 6 4 385.8 5.6 6 5 451.9 6.7 6 6 212.6 3.8 6 7 345.2 6.4 6 8 163.1 4.4 6 10 355.3 12.7 6 11 381.9 5.6 96 12 72.4 8.9 96 13 598.6 8.9 9 6 14 167.8 5.9 9 6 15 264.2 4.8 9 6 16 263.5 5.1 9 6 17 284.2 4.7 9 6 18 221.2 4.1 9 6 19 119.0 4.9 9 6 20 217.3 9 6 21 89.8 9 6 22 77.2 6.8 9 6 23 76.6 9 6 24 197.2 5.4 9 6 25 257.9 10.5 9 6 26 32.9 13.9 9 6 27 162.9 9.9 9 6 28 105.6 9.1 9 6 29 101.4 9.2 9 6 30 28.6 13.4 9 7 0 521.0 9.4 9 7 1 494.8 7.8 9 7 2 164.3 3.8 9 7 3 323.8 9 7 4 335.9 4.8 9 7 5 466.2 7.1 9 7 6 288.4 5.1 9 7 7 325.2 8.4 9 7 8 161.1 4.4 9 7 9 405.2 19.1 9 7 10 270.2 4.9 9 7 11 367.6 5.8 9 7 12 79.3 9 7 13 106.9 8.7 9 7 14 230.5 4.1 9 7 15 202.6 3.9 9 7 16 395.3 5.7 9 7 17 170.7 3.8 9 7 18 145.3 4.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -138- 150.7 4.5 172.9 4.8 186.3 4.2 90.4 7.3 195.5 5.2 24.4 11.7 198.4 8.2 133.3 6.3 25.4 12.6 143.0 6.6 91.6 9.5 317.2 6.7 468.3 8.1 138.0 3.8 461.4 7.0 365.4 5.4 527.0 7.7 501.1 7.9 302.2 4.8 690.3 9.9 161.9 4.6 254.8 4.5 20.7 10.2 174.6 4.1 260.2 4.5 230.6 4.6 205.9 5.2 36.5 11.9 171.7 3.8 121.1 4.3 126.8 5.0 160.6 4.3 63.2 13.8 18.1 9.0 178.5 5.7 21.1 10.6 56.7 14.0 96.1 11.7 135.9 7.2 260.2 5.3 553.0 9.9 196.5 4.2 186.7 3.4 629.8 8.3 118.3 7.6 372.4 6.8 472.4 17.6 368.7 7.0 I347.7 5.4 389.2 5.8 200.0 4.9 350.3 5.8 1159.7 6.2 ;104.1 6.2 i188.9 3.6 127.3 4.5 1140.7 4.0 149.6 4.1 74.7 7.4 1 152.3 4.3 !17.0 8.6 3 110.0 6.2 1 102.9 8.7 69.0 13.8 5112.1 8.9 7 67.5 14.2 3 22.5 11.1 ?38.5 14.6 3 583.7 8.6 1 289.9 4.4 2 271.5 4.1 3 375.5 5.4 143.8 10.9 392.0 6.4 155.2 6.2 538.8 8.0 135.4 4.7 116.8 4.6 126.4 4.8 472.4 7.0 95.2 6.6 17.5 8.7 193.9 4.4 218.8 4.1 223.2 4.3 165.9 4.4 140.5 4.7 35.2 15.4 181.3 4.3 229.5 15.8 156.6 6.3 109.3 8.8 135.8 8.2 113.8 8.2 210.1 5.6 85.8 4.2 121.2 4.0 396.4 7.1 404.0 5.8 99.8 5.0 173.4 3.7 27.5 13.3 114.2 5.3 421.4 6.5 432.0 6.5 307.1 5.3 268.9 4.8 75.0 6.5 219.0 4.1 254.7 4.2 156.4 4.1 179.1 3.9 74.6 6.8 P236.3 4.6 161.5 4.4 79.2 8.2 159.0 5.3 131.2 5.0 531.6 47.8 86.1 11.0 137.3 5.5 26.5 13.2 1 46.3 14.9 21.3 10.7 286.2 6.5 462.9 8.3 255.7 7.3 17.3 8.2 243.1 4.0 232.5 3.9 201.3 4.0 226.8 4.5 3337.5 5.5 1 334.9 5.2 2 18.8 8.8 3 368.5 6.0 4 263.1 4.5 5 307.5 4.3 6 47.1 13.3 7 107.8 5.8 8 115.5 4.7 9 155.4 5.4 0 232.1 4.1 1 171.7 4.9 114.8 5.2 29.8 13.1 170.2 4.7 167.7 5.1 110.4 8.9 144.1 6.4 337.2 4.7 113.9 3.5 470 .8 7.2 315 .0 19.4 129.8 5.0 478.4 8.3 342.1 5.1 563.2 8.8 356.9 5.6 312.9 6.0 595 .4 8.6 301.4 5.1 193.2 3.8 86.4 5.9 128.6 3.8 38.1 12.3 124.9 4.2 108.3 6.0 154 .6 3.9 131.1 5.2 48.6 14.9 144.9 4.9 200.6 13.6 68.5 10.1 47.0 13.1 75.5 11.2 74.5 12.3 54.2 14.6 383 .1 13.6 342 .4 13.7 267.3 7.9 485.8 12.5 270.0 4.4 351.7 5.3 102.4 4.5 190.1 4.2 819.5 12.2 37.5 10.9 215.9 4.4 444.5 7.1 200.6 4.0 284.8 4.6 142.0 3.7 127.4 3.8 87.1 5.4 81.6 5.7 85.8 5.7 I108.1 6.0 1 197.6 4.1 81.1 7.9 t119.9 5.3 1244.1 11.9 i57.3 14.2 i185.1 5.7 7134.3 10.5 49.0 16.4 257.7 4.5 182.2 3.8 209.3 5.5 176.1 4.2 68.9 7.7 297.8 5.3 506.2 6.9 312.2 4.7 109.5 4.7 I378.1 5.8 283.5 4.7 329.8 5.3 127.5 4.3 65.0 6.4 70.4 6.2 80.0 8.4 92.2 5.1 53.6 10.3 53.9 10.5 181.8 4.1 119.0 5.1 212.8 4.2 63.1 15.2 118.8 7.6 64.2 12.2 86.3 7.6 185.3 5.8 99.0 108.3 9.2 74.3 5.9 387.0 6.8 332.2 4.9.

294.3 232.6 4.1 214.7 3.7 257.2 375.8 7.2 184.2 4.1 200.9 4.4 103.9 4.8 163.0 4.7 273.3 18.6 8.8 135.5 4.3 197.3 3.7 241.8 210.3 3.9 160.1 4.2 135.2 4.2 I181.3 5.1 .118.7 6.6 359.4 9.3 143.4 5.4 58.6 11.1 59.8 15.3 137.9 74.4 11.6 322.3 6.1 280.3 302.1 4.8 334.5 6.4 145.2 4.2 168.3 3.2 254.4 3.9 149.6 200.6 3.7 145.4 4.1 3149.0 3.8 1 348.2 6.6 2 132.6 4.4 3 161.2 3.8 4 56.7 7.4 5 224.2 4.3 6 40.7 11.8 7 48.0 10.8 8 55.7 9 34.3 12.5 0 194.1 3.9 1 27.9 13.0 2 151.6 4.9 3 167.5 4.6 4 101.5 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -1319- 9 1725 188.3 5.7 9 20 15 97.3 4.5 9 23 11 1 62.2 3.9 9 26 11 18.2 8.4 9 17 26 20.0 9.7 9 20 16 72.3 7.0 9 23 12 287.0 5.2 9 26 12 87.9 6.4 9 17 27 18.7 9.4 9 20 17 64.6 8.8 9 23 13 90.6 5.1 9 26 13 85.7 8.9 9 18 0 86.8 4.4 9 20 18 78.8 6.8 9 23 14 125.0 4.5 9 26 14 136.4 3.8 9 18 1 256.8 4.7 9 20 19 57.8 8.6 9 23 15 162.1 3.7 9 26 15227.5 14.1 9 18 2 101.7 5.7 9 20 20 348.5 11.8 9 23 16 133.6 4.7 9 26 16 64.4 10.0 9 18 3 219.2 5.0 9 20 21 46.0 11.9 9 23 17 26 .7 11.8 9 26 17 154.5 5.1 9 18 4 79.0 4.3 9 20 22 157.8 4.8 9 23 18 240.2 11.7 9 26 18 169.1 6.6 9 18 5 438.7 6.5 9 20 23 81.2 7.8 9 23 19 197.5 4.3 9 26 19 52.8 12.0 9 18 6 98.9 4.9 9 20 24 75.0 9.8 9 23 21 111.6 7.6 9 26 20 26.3 11.2 9 18 7 324.6 4.8 9 20 25 24.1 11.5 9 23 22 155.6 5.6 9 26 21 124.7 9 18 8 76.6 5.2 9 20 26 89.4 12.5 9 23 23 130.6 5.8 9 26 22 83.6 6.4 9 18 9 264.5 4.4 9 21 0 179.2 3.0 9 23 24 30 .5 13.0 9 27 0 123.8 4.3 9 18 10 129.3 4.0 9 21 1 120.2 7.3 9 24 0 355.4 9.0 9 27 1 128.2 4.1 9 18 11 143.8 4.3 9 21 2 343.2 5.5 9 24 1 265.6 4.5 9 27 2 135.6 3.1 9 18 12 123.1 3.8 9 21 3 219.2 3.6 9 24 2 296.0 5.2 9 27 3 109.0 3.8 9 18 13 114.1 4.0 9 21 4 424.1 5.8 9 24 3 117.2 4.3 9 27 4 166.3 4.1 9 18 14 211.3 3.7 9 21 5 287.1 4.7 9 24 4 25.2 9.5 9 27 5 214.3 3.7 9 18 15 50.4 8.2 9 21 6 205.9 3.3 9 24 5 116.3 3.3 9 27 6 236.4 3.7 9 18 16 139.0 3.7 9 21 7 126.4 4.1 9 24 6 15.1 7.2 9 27 7 138.3 3.2 9 18 17 49.0 11.6 9 21 8 154.4 3.5 9 24 7 19.2 8.5 9 27 8 70.6 6.2 9 18 18 206.3 4.6 9 21 9 398.4 5.4 9 24 8 67.6 5.1 9 27 9 206.0 9 18 19 216.5 4.1 9 21 10 263.1 4.4 9 24 9 192.7 3.2 9 2710 125.4 3.7 9 18 20 92.5 5.9 9 21 11 366.1 5.2 9 24 10 153.4 3.3 9 27 11 35.0 9 18 21 413.7 17.6 9 21 12 39.4 10.8 9 24 11 148.7 3.7 9 27 12 83.9 4.9 9 18 22 83.1 7.0 9 21 13 127.3 4.2 9 24 12 166.9 3.8 9 27 14 276.6 13.2 9 18 23 71.2 12.9 9 21 14 150.5 3.7 9 24 13 37.3 10.6 9 27 15 100.7 6.1 9 1824 134.1 7.6 9 21 15 75.5 8.2 9 2414 181.6 3.8 9 27 16267.1 4.6 9 18 25 23.4 11.2 9 21 16 121.6 4.5 9 24 15 63.2 7.4 9 27 17 87.4 9 18 26 18.0 8.9 9 21 17 52.7 12.3 9 24 16 193.2 4.2 9 27 18 80.1 7.8 9 19 0 139.9 4.7 9 21 18 61.3 7.9 9 24 17 369.7 14.8 9 27 19 98.6 6.4 9 19 1 192.7 3.7 9 21 19 160.5 15.1 9 24 18 229.8 4.1 9 27 20 27.1 11.7 9 19 2 228.5 3.6 9 21 20 183.4 4.9 9 24 19 38.3 13.4 9 27 21 103.3 6.9 9 19 3 91.3 4.0 9 21 21 163.3 5.7 9 24 20 91.6 8.3 9 28 0 170.3 4.4 9 19 4 317.1 4.4 9 21 22 205.2 4.7 9 24 21 84.9 6.6 9 28 1 211.0 9 19 5 46.0 9.3 9 21 23 174.1 7.2 9 24 22 54.0 11.7 9 28 2 152.8 4.1 9 19 6 234.5 4.0 9 21 24 83.8 9.4 9 24 23 99.6 6.4 9 28 3 152.3 3.3 9 19 7 69.0 5.2- 9 21 25 110.4 7.3 9 25 0 141.1 4.2 9 28 4 59.4 8.2 9 19 8 85.3 5.7 9 22 0 228.6 4.2 9 25 1 197.1 3.9 9 28 5 61.9 4.7 9 19 9 120.4 3.7 9 22 1 349.8 5.2 9 25 2 107.1 5.2 9 28 6 68.2 5.2 9 19 10 228.4 3.6 9 22 2 49.9 5.3 9 25 3 204.7 3.7 9 28 7 188.5 3.4 9 19 11 109.7 4.7 9 22 3 504.0 10.5 9 25 4 136.8 5.9 9 28 8 98.5 3.9 9 19 12 127.2 3.7 9 22 4 201.3 3.9 9 25 5 186.9 3.6 9 28 9 155.9 9 19 13 131.9 3.7 9 22 5 389.9 5.9 9 25 6 82.5 4.8 9 28 10 98.8 4.7 9 19 14 181.7 3.6 9 22 6 206.9 3.9 9 25 7 66.2 5.1 9 28 11 135.6 3.7 9 19 15 270.8 4.2 9 22 7 327.6 5.9 9 25 8 121.5 3.4 9 28 12 81.8 7.2 9 19 16 168.5 4.1 9 22 8 103.8 3.5 9 25 9 68.6 6.7 9 28 13 184.1 24.7 9 19 17 78.8 6.3 9 22 9 136.9 3.2 9 25 10 209.4 3.6 9 28 14 141.2 9 19 18 279.1 4.6 9 22 10 55.0 7.5 9 25 11 37.2 9.2 9 28 15 60.9 8.6 9 19 19 95.2 9.4 9 22 11 247.4 4.2 9 25 12 70.5 5.8 9 28 16 231.0 9 19 20 19.6 9.7 9 22 12 265.5 4.1 9 25 13 160.0 3.7 9 28 17 55.6 10.6 9 1.9 21 155.1 7.6 9 22 13 62.3 7.6 9 25 14 228.7 3.7 9 28 18 65.0 7.8 9 19 22 180.3 6.3 9 22 14 224.3 3.9 9 25 15 214.0 4.0 9 28 19 39.7 15.8 9 19 23 127.5 6.5 9 22 15 148.3 3.7 9 25 16 268.2 10.5 9 28 20 66.1 9 19 24 62.4 10.3 9 22 16 99.6 5.8 9 25 17 229.6 4.2 9 29 0 140.5 4.2 9 19 25 210.3 5.0 9 22 17 163.8 4.3 9 25 18 132.2 6.5 9 29 1 116.1 5.9 9 19 26 159.4 6.2 9 22 19 131.7 7.2 9 25 19 210.2 4.2 9 29 2 187.4 4.3 9 20 0 276.8 5.3 9 22 20 23.8 10.9 9 25 20 103.3 6.2 9 29 3 133.3 9 20 1 217.1 3.7 9 22 21 101.0 6.1 9 25 21 55.2 11.9 9 29 4 210.4 9 20 2 159.4 4.7 9 22 23 73.5 9.5 9 25 22 49.9 15.1 9 29 5 198.2 4.6 9 20 3 179.5 3.6 9 22 24 109.0 7.8 9 25 23 89.4 11.8 9 29 6 166.4 9 20 4 131.8 3.8 9 23 0 632.6 11.1 9 26 0 250.2 4.5 9 29 7 116.6 9 20 5 199.4 3.3 9 23 1 230.7 3.9 9 26 1 134.0 3.2 9 29 8 223.1 3.7 9 20 6 64.5 5.6 9 23 2 397.9 6.7 9 26 2 132.3 3.9 9 29 9 104.3 9 20 7 227.7 4.6 9 23 3 413.7 7.9 9 26 3 182.0 3.5 9 29 10 219.5 9 20 8 66.3 7.4 9 23 4 209.1 3.2 9 26 4 160.5 4.2 9 29 11 192.6 12.4 9 20 9 138.5 3.5 9 23 5 129.5 4.1 9 26 5 66.3 6.0 9 29 12 39.3 13.2 9 2010 134.3 3.6 9 23 6 156.7 3.1 9 26 6 173.5 3.2 9 2913 187.7 3.8 9 20 11 16.8 8.1 9 23 7 173.1 4.0 9 26 7 134.1 3.6 9 29 14 110.8 5.9 9 20 12 121.1 3.8 9 23 8 93.7 4.2 9 26 8 134.9 3.6 9 29 15 146.0 9 20 13 112.1 3.9 9 23 9 60.1 5.7 9 26 9 104.0 4.2 9 29 16 69.2 9 2014 125.1 3.6 9 2310 173.5 3.5 9 2610 131.0 3.6 9 2917 131.7 5.8 SUBSTITUTE SHEET (RULE 26)/ WO 99/1 0379 -140- 59.2 12.9 123.0 '5.1 121.2 6.4 176.1 3.5 172.7 4.5 132.5 3.9 168.0 4.8 96.6 4.7 152.2 4.4 38.0 9.3 172.9 3.3 187.6 3.6 69.6 16.6 261.2 15.8 72.8 7.1 98.7 4.3 22.7 10.5 111.1 6.5 112.6 6.1 101.8 4.8 191.1 4.1 140.5 8.6 61.3 10.0 23.7 9.7 35.5 11.1 101.9 5.1 66.8 4.4 297.5 7.5 56.5 5.8 105.8 7.8 92.7 20.5 157.9 4.4 43.0 8.3 212.8 4.5 176.7 3.9 231.8 4.1 18.6 9.0 87.1 5.9 44.8 12.3 106.8 4.4 49.8 13.4 22.0 10.0 122.9 5.1 76.4 6.7 128.2 8.8 212.6 16.7 276.6 12.7 226.2 6.2 176.1 3.9 95.7 4.1 124.1 3.9 106.7 5.1 216.2 4.5 167.7 4.1 195.8 4.0 112.5 5.3 221.1 4.5 90.4 6.5 81.1 7.4 161.9 9.0 34.5 10.9 33.7 11.9 113.3 4.8 162.3 4.0 57.8 5.1 127.3 4.7 183.7 3.2 137.0 3.8 146.3 3.4 114.7 4.5 1 214.5 4.0 S69.7 7.4 155.3 4.9 124.5 4.9 105.3 4.6 106.6 4.5 71.1 6.3 248.5 5.1 125.1 4.7 47.4 13.0 88.8 6.0 24.3 10.8 32.4 11.1 219.8 3.8 19.7 9.1 85.3 5.6 185.5 3.8 61.8 9.3 56.0 9.1 106.5 4.9 94.9 7.1 188.2 4.9 83.4 7.5 59.0 7.2 43.9 10.3 46.3 10.6 197.0 4.9 66.5 7.0 215.3 4.2 149.5 3.5 56.7 7.5 69.4 9.6 107.8 4.9 168.2 7.8 161.3 4.6 103.5 4.6 130.9 4.1 158.9 4.0 104.1 5.2 96.3 5.4 137.4 4.9 123.4 4.8 77.8 7.0 90.2 7.0 82.4 5.2 152.8 4.6 40.0 10.8 45.6 9.5 83.4 5.7 181.7 4.1 86.5 5.3 19.7 8.9 18.0 8.7 96.8 5.6 108.6 4.3 126.1 5.8 197.7 4.6 218.2 5.0 102.6 4.7 163.3 5.2 136.2 4.5 64.2 9.9 172.0 8.1 28.0 12.0 11.9 8.8 16.9 11.5 538.1 10.4 90.7 10.2 807.9 14.6 57.8 18.8 402.9 9.0 178.6 6.6 I44.0 19.9 3 103.5 16.7 276.3 7.1 247.4 6.3 17.4 12.3 84.5 19.2 147.9 6.8 105.8 12.4 84.8 19.8 158.9 5.8 187.7 6.0 193.3 6.2 260.2 6.6 32.5 17.1 164.6 7.0 35.8 23.9 32.7 19.3 60.4 23.1 251.1 7.7 22.3 15.6 137.4 14.5 496.7 7.1 584.0 8.9 505.2 6.7 94.5 4.5 347.3 4.9 16.5 8.3 166.0 10.3 495.7 7.5 549.9 12.4 368.2 8.2 26.3 12.7 204.2 5.0 127.3 4.8 214.3 4.6 17.7 8.9 260.2 4.4 157.8 4.9 102.1 6.8 147.9 4.7 63.2 8.7 82.3 7.9 71.0 8.1 98.8 5.8 142.7 5.4 29.4 14.7 118.7 6.7 64.0 14.6 140.7 10.4 182.8 7.0 82.2 13.3 190.1 3.6 264.6 4.0 821.1 13.0 351.1 5.7 330.3 5.0 343.2 7.0 476.3 7.8 181.0 4.1 347.9 11.5 165.8 4.6 223.1 5.1 606.4 8.4 154.0 4.1 196.1 4.3 121.8 5.5 i72.7 9.0 i185.4 4.3 89.1 10.0 1165.9 4.1 147.8 4.0 107.3 5.5 1 165.5 4.1 Z~ 47.3 11.5 PCT/GB98/02542 0 2 23 73.1 9.1 0 2 24 128.2 35.5 0 2 25 159.6 0 2 26 126.7 9.3 0 2 27 157.0 6.6 0 2 28 199.9 5.7 0 2 29 74.3 11.4 0 3 0 384.8 5.6 0 3 1 244.8 0 3 2 403.0 6.8 0 3 3 344.0 6.4 0 3 4 384.4 0 3 5 373.9 22.8 0 3 6 513.2 9.4 0 3 7 278.0 9.2 0 3 8 644.6 22.0 0 3 9 369.9 5.9 0 3 10 203.7 0 3 11 437.8 0 3 12 189.5 4.4 0 3 13 211.6 4.8 0 3 14 228.0 4.4 0 3 15 189.0 4.2 0 3 16 290.8 4.8 0 3 17 183.9 6.4 0 3 18 167.7 4.2 0 3 19 222.0 4.7 0 3 20 48.9 12.1 0 3 21 132.1 0 3 22 208.9 4.6 0 3 23 77.2 0 3 24 140.8 16.0 0 3 25 195.6 4.9 0 3 26 135.5 7.6 0 3 27 226.5 5.4 0 3 28 134.1 7.6 .0 3 29 113.8 .0 4 0 23.8 10.1 .0 4 1 307.6 4.7 10 4 2 19.0 8.9 [0 4 3 196.1 3.7 0 4 4 671.7 9.6 10 4 5 383.4 7.1 10 4 6 199.2 4.1 10 4 9 210.0 4.9 10 4 10 164.2 6.7 10 4 11 235.0 10 4 12 372.7 6.3 10 4 13 47.5 12.2 10 4 14 25.3 11.5 10 4 15 174.8 4.2 10 4 16 245.6 4.9 10 4 17 264.9 4.7 10 4 18 97.7 10 4 19 106.6 5.8 10 4 20 171.3 4.2 10 4 21 94.9 8.1 10 4 22 130.8 10 4 23 100.9 10 4 24 270.0 12.9 10 4 25 131.1 7.4 10 4 26 168.8 7.9 10 4 27 162.3 7.4 10 4 28 118.7 9.6 10 4 29 121.5 10 5 0 173.0 3.7 10 5 1 402.2 6.7 10 5 2 402.5 7.9 10 5 3 236.3 4.8 10 5 4 110.6 10.1 10 5 5 282.2 6.6 10 5 6 118.4 5.7 SUBSTITUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -141- 531.9 15.3 337.2 5.7 216.2 4.6 315.1 6.0 215.0 4.1 106.8 5.6 267.7 4.6 231.1 4.5 350.1 5.5 359.8 5.5 165.9 4.2 64.3 8.5 111.3 6.6 221.0 4.4 32.7 12.6 92.8 8.2 60.9 9.6 448.6 11.8 25.5 12.0 135.2 6.8 178.0 6.0 163.4 6.8 44.7 17.8 166.5 3.3 188.3 3. 3 294.5 5.5 232.5 5.3 593.5 7.9 45.4 13.2 272.9 4.9 223.6 4.6 75.8 10.4 52.7 10.6 407.0 6.3 210.6 4.9 338.1 5.6 119.7 4.8 125.0 7.7 206.7 4.3 105.8 4.8 I106.9 5.9 1 178.4 5.0 84.0 8.2 222.6 4.6 106.4 5.8 1 367.4 12.4 i254.8 6.2 i195.1 6.1 1 147.8 10.6 397.1 12.8 59.7 18.0 164.4 7.5 164.0 4.5 354.5 7.2 240.6 5.6 *36.4 11.2 239.0 4.2 286.5 14.2 91.7 9.2 1521.8 8.4 )251.7 4.6 0 260.7 5.7 1 372.0 5.4 2 197.4 4.3 3 521.3 7.5 4 104.0 5.4 121.1 6.2 6 288.2 4.7 7 110.1 6.0 8 125.2 4.4 9 117.4 4.6 D0 110.6 5.4 205.5 4.3 86.4 6.5 122.6 5.5 42.5 19.9 130.1 6.4 131.6 7.1 117.3 9.2 160.9 6.1 225.1 5.7 391.0 5.8 464.2 7.2 188.7 5.4 17.4 8.8 38.4 11.7 282.4 4.6 209.3 5.4 281.6 4.8 141.0 4.2 317.3 4.9 250.9 4.4 288.9 4.6 178.4 4.1 211.9 4.1 26.7 12.5 114.3 7.1 168.1 3.8 84.0 6.4 63.1 9.6 86.3 6.3 20.8 10.4 21.9 10.6 200.2 6.4 38.6 15.7 152.3 6.1 519.6 7.9 314.9 6.3 74.3 6.2 96.5 6.9 460.7 23.8 253.2 24.8 428.6 6.1 354.7 5.2 205.6 4.7 184.0 6.2 179.8 4.1 1 237.8 5.0 350.6 5.4 3 26.7 11.3 1 158.0 4.8 5 208.1 4.3 5 84.9 7.1 7 98.8 5.4 8 129.0 5.3 916.3 8.2 D 111.6 4.9 1 78.9 10.5 2 136.8 5.2 3 30.8 15.6 4 99.6 8.4 5 117.6 6.5 6 38.4 16.4 7 26.1 12.5 8 34.3 14.5 0 123.6 6.5 1 391.1 12.3 2 54.8 13.7 3 268.1 22.2 4 195.9 23.3 6 402.8 5.8 7 307.7 4.8 8 121.2 4.8 9 85.3 7.6 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 t0 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 I0 10 10 1C 10 10 14 1( 1H 10 10 4 10 11 1 10 12 3 10 13 1 10 14 1 10 15 2 10 16 10 17 10 18 1 10 19 1 10 20 10 21 1 10 22 1 10 23 4 10 24 1 10 25 10 26 10 27 10 28 1 11 0 3~ 11 1 5' 11 2 5I 11 4 32 11 5 6 11 6 1~ 11 7 3' 11 8 1i 11 9 1' 11 10 1 11 11 2 11 12 2 11 13 1 11 14 1 11 15 1 11 16 1 11 17 11 18 1 11 19 1 11 20 11 21 1 11 22 11 23 11 24 11 25 11 26 11 27 11 28 12 0 12 1 1 P12 2 I12 3 2 12 4 2 I12 5 2 I12 6 I12 7 5 I12 8 12 9 1 12 10 12 11 12 12 12 13 12 14 0 12 15 0 12 16 0 12 17 0 12 18 0 12 19 0 12 20 0 12 21 0 12 22 o 12 23 0 12 24 18.1 03.6 35.5 99.9 93.6 37.7 ~0.0 1.8 35.7 65.1 14.6 1 58.9 19.3 24.5 61.2 Z8.3 1 97.5 1 22.4 1 18.5 58.7 1 45.4 2 85.0 1 51.6 4.8 8 25.9 40.3 66.2 07.3 02.1 ~51.7 ~65.0 92.6 32.7 45.5 71.3 63.3 108.5 150.6 ~01.6 193.6 127.6 Z46.6 76.3 195.1 148.0 138.2 20.6 18.5 19.4 19.4 ~17.8 ~20.4 ~88.7 61.3 ~03.2 96.5 181.8 105.1 198.6 325.2 142.2 190.7 34.1 200.1 66.2 78.1 57.6 142.0 97.7 126.2 112.6 34.2 8.1 5.1 5.7 4.5 3.9 5.2 7.2 4.6 4.6 2.2 5.2 5.6 12.1 5.8 3.7 1.2 0.9 10.1 1.2 22.0 7.7 5.3 .5 5.0 5.8 4.5 5.2 6.0 4.4 4.5 4.0 5.0 3.9 4.2 8.0 5.3 5.2 4.3 4.3 6.5 25.1 9.7 6.3 6.3 8.0 10.4 8.7 4.6 9.0 4.0 4.3 5.4 6.5 7.5 5.0 3.9 5.7 4.2 4.8 3.9 4.0 11.4 4.3 7.7 7.0 9.5 5.9 6.1 7.2 6.2 13.9 10 1: 10 1: 10 1: 10 1: 10 1L 10 1: 10 1, 10 1L 10 1L 10 1.

10 1I 10 1.

10 1 10 1 10 1 10 1 10 1 10 1 t0 1 10 1 10 1 10 1 10 1 10 I 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 i 101 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 108.3 8.6 71.5 11.3 45.1 15.2 56.9 24.4 407.7 6.6 209.0 4.6 173.8 3.8 157.9 252.1 4.2 91.6 5.6 484.6 7.1 377.5 144.6 4.8 368.0 5.8 86.4 272.7 4.3 86.2 7.1 244.8 136.1 4.1 209.0 3.8 178.4 4.4 97.5 5.6 111.7 88.8 I45.7 12.3 19.4 9.6 305.6 13.2 96.2 10.1 220.1 5.3 117.8 6.8 150.7 114.0 7.9 399.1 8.2 176.5 3.6 264.8 4.1 450.7 8.1 318.0 90.5 6.4 186.2 3.8 219.5 489.6 7.4 135.5 3226.2 1 179.8 4.1 2 157.1 4.4 3 22.6 10.2 4 73.2 6.2 5' 75.5 10.5 7 69.1 10.8 8 159.4 4.1 9 93.1 5 0 81.1 1 94.9 6.2 2 151.0 23.7 3 92.4 7.8 4 40.0 14.8 5 87.7 6 184.6 6.4 7 26.0 12.3 38.3 8.9 1 170.2 4.8 2 275.8 4.3 3 223.8 3.9 4 254.9 4.6 5 454.3 6.8 6 141.9 3.8 7 360.9 5.3 8 198.5 4.2 9 168.7 5.3 [0 176.2 11 293.0 5.1 12 117.5 SUBSTITUTE SHEET (RULE WO 99/10379 -142- 153.0 4.7 194.6 4.0 61.1 8.2 78.5 6.7 56.4 10.3 72.3 9.3 185.6 4.6 167.3 5.4 78.9 12.2 44.8 13.5 96.9 7.8 159.0 6.4 41.0 16.2 187.3 6.5 25.8 12.5 244.1 4.5 149.7 4.3 384.8 7.0 123.0 4.3 313.0 4.8 282.6 4.7 53.1 12.0 24.0 10.3 217.1 3.9 177.0 3.8 203.4 4.4 54.1 10.6 157.5 4.7 179.5 4.3 78.0 6.2 84.8 5.8 69.5 8.7 77.7 5.8 109.3 7.8 120.2 5.7 94.3 6.7 318.8 12.5 235.6 4.7 55.6 13.7 28.1 12.8 101.7 8.7 31.8 13.6 168.7 4.0 127.6 3.7 104.0 9.4 126.1 3.8 196.6 3.5 275.7 4.3 164.0 4.3 162.3 4.2 160.4 4.5 260.4 4.0 153.7 3.6 248.0 4.2 73.7 7.0 122.1 4.2 233.7 4.1 164.1 4.9 147.2 4.7 116.1 6.1 148.7 4.2 I129.2 4.7 131.7 5.1 216.4 4.7 124.3 11.3 182.2 5.2 i138.6 7.2 130.6 8.0 153.7 3.8 352.6 5.5 249.6 4.0 328.3 5.9 10 18 10 18 10 18 10 18 10 18 10 18 1 10 18 1 10 18 1 10 181 10 18 1 10 18 1 10 18 1 10 18 10 18 1 10 18 10 18 10 18 10 18 10 18 10 18 10 18 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 19 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 10 20 160.4 3.6 280.9 4.4 254.9 4.4 217.3 4.0 72.4 5.4 93.4 5.0 242.2 4.0 90.4 4.9 238.3 3.7 56.6 11.6 182.1 3.9 179.3 4.0 42.9 12.3 92.6 7.2 148.6 4.5 335.1 24.3 45.0 12.2 20.3 9.8 121.3 8.4 107.4 9.8 98.3 10.3 208.3 5.1 175.7 3.3 46.6 7.5 401.9 6.4 290.3 4.3 144.1 3.9 513.7 8.0 206.5 4.2 42.2 11.6 76.9 5.0 214.3 3.6 26.4 10.8 122.8 4.8 153.6 3.6 125.5 3.8 96.6 4.6 210.9 4.1 300.3 4.8 191.2 4.2 304.9 11.2 233.8 4.6 111.5 6.6 125.3 5.9 217.4 4.9 132.3 7.2 31.2 13.5 117.8 3.8 239.1 5.2 382.0 6.4 352.8 5.8 234.6 4.3 305.8 4.4 72.4 6.0 148.5 3.7 149.5 3.3 91.0 4.2 I182.1 3.6 164.1 3.7 30.3 10.7 184.8 6.1 1 157.7 3.9 i65.6 10.2 i106.4 6.2 1 118.9 4.9 316.7 8.4 57.9 16.6 22.9 10.9 1 18.9 9.5 2 72.1 9.6 3 51.9 13.6 4 87.2 7.6 10 20 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 21 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 22 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 10 23 25 35.8 1 0 170.8 1 320.6 2 210.0 3 502.4 4 353.8 5 289.3 6 223.0 7 90.4 4 8 392.3 9 280.6 10 75.4 11 86.3 13 57.6 14 160.1 15 154.5 16 98.9 17 169.4 18 398.3 19 52.6 1 20 79.8 21 152.3 22 144.5 23 26.51 24 28.11 0 72.0 1 282.2 2 420.2 3 348.7 4 397.7 5 224.4 6 81.7 7 164.9 8 136.2 9 176.2 10 144.4 11 162.5 12 134.7 13 88.1 14 127.4 15 255.9 16 149.1 17 184.0 18 237.0 19 52.4 20 88.9 21 118.2 22 24.3 23 95.6 0 150.2 1 367.9 2 132.0 3 296.9 4 131.7 5 52.9 6 94.5 7 132.6 8 192.4 9 113.4 10 176.4 11 85.3 12 152.0 13 71.2 14 287.1 15 110.0 *16 46.6 *17 112.7 18 183.0 19 142.2 20 78.8 21 107.8 22 70.4 6.7 3.5 6.1 3.5 6.8 5.9 4.3 5.1 .7 5.7 4.4 5.0 5.5 6.8 4.2 3.7 5.6 5.2 15.1 1.9 7.7 4.8 7.0 2.1 3.1 1.4 5.0 8.9 7.0 6.0 4.4 1.6 3.7 4.3 3.5 3.5 3.6 3.8 5.4 6.2 4.1 4.4 11.7 4.6 13.3 7.5 6.6 11.9 8.4 2.9 6.1 3.6 4.9 4.6 7.6 9.3 4.1 3.7 3.9 3.5 4.7 4.1 7.5 4.7 5.0 18.5 8.8 5.8 4.5 11.5 7.0 10.5 PCT/GB98/02542 D 23 23 150.1 5.4 D 24 0 203.8 D 24 1 395.2 7.2 D 24 2 63.1 8.1 D 24 3 150.3 2.9 D 24 4 132.1 2.9 D 24 5 133.1 3.8 D 24 6 216.7 3.6 3 24 7 133.3 3.8 D 24 8 87.8 4.3 D 24 9 155.0 3.4 0 24 10 99.7 5.8 0 24 11 193.5 3.7 0 24 12 124.3 4.1 0 24 13 230.9 0 24 14 100.8 4.4 0 24 15 20.7 10.4 0 24 16 170.6 6.4 0 24 17 147.5 0 24 18 219.7 5.1 0 24 19 223.3 4.7 0 24 20 192.4 4.2 0 24 21 120.6 5.1 0 24 22 151.2 5.1 0 25 0 237.3 5.1 0 25 1 18.6 0 25 2 171.3 0 25 3 279.7 6.4 0 25 4 236.2 4.1 0 25 5 43.1 6.1 0 25 6 84.2 4.1 0 25 7 148.5 3.4 0 25 8 192.5 3.7 0 25 9 137.8 3.8 0 25 10 100.1 0 25 11 40.0 11.2 0 25 12 107.4 0 25 13 173.2 0 25 14 46.2 19.8 0 25 15 52.8 17.3 0 25 16 55.9 8.3 0 25 17 225.2 4.4 0 25 18 134.2 4.9 0 25 19 107.4 5.8 0 25 20 172.4 5.1 0 25 21 72.4 12.0 0 25 22 107.9 6.3 0 26 0 87.7 4.6 0 26 1 218.3 4.6 0 26 2 221.9 3.9 0 26 3 238.3 5.3 0 26 4 129.1 4.4 0 26 5 297.7 0 26 6 91.9 0 26 7 74.0 4.6 .0 26 8 180.0 0 26 9 60.1 [0 26 10 51.0 0 26 11 122.1 10 26 12 94.8 4.9 10 26 13 147.4 16.1 10 26 14 28.1 13.0 10 26 15 165.0 10 26 16 34.6 12.6 10 26 17 216.5 4.4 10 26 18 69.8 11.6 10 26 19 41.2 14.1 10 26 20 64.6 15.1 10 26 21 57.8 12.1 10 27 0 23.3 10 27 1 66.9 4.9 10 27 2 83.2 SUBSTI I U I SHEET (RULE 26) WO 99/10379 -143- 27 3 203.1 3.3 27 4 148.8 3.6 27 5 114.4 5.4 27 6 118.8 4.3 27 7 118.1 4.7 27 8 67.8 6.4 27 9 52.5 6.9 27 10 70.4 5.9 27 11 121.6 4.5 27 12 196.4 17.0 27 13 16.4 8.2 27 14 87.7 5.1 27 15 75.8 6.6 27 16 130.6 6.4 27 17 113.2 5.9 27 18 28.5 11.9 27 19 121.0 7.4 2 7 20 122.2 6.7 28 0 62.1 4.7 28 1 112.2 34 28 2 89.7 6.0 28 3 133.8 4.9 28 4 101.3 3.0 28 5 87.8 5.3 28 6 112.6 4.9 28 7 159.7 3.9 28 8 163.4 3.3 28 9 48.4 10.4 28 12 311.3 5.6 28 13 71.4 8.1 28 14 90.7 6.4 28 15 58.6 11.5 28 16 81.7 7.1 28 17 44.5 13.3 28 18 19.8 9.7 28 19 17.4 8.7 29 0 163.2 4.5 29 1 41.5 6.5 29 2 129.7 4.6 29 3 189.5 3.7 29 4 147.5 3.6 29 5 195.7 5.1 29 6 31.8 12.2 29 7 174.2 4.1 29 8 119.6 4.2 29 9 240.0 12.9 29 10 139.8 5.5 29 11 58.9 9.8 29 12 144.4 4.2 29 13 22.1 9.9 29 14 179.9 4.2 '29 15 196.5 4.2 29 16 114.6 5.5 29 17 141.8 5.0 29 18 131.3 5.6 30 0 109.0 3.7 30 1 77.4 6.1 30 2 62.0 8.5 30 3 132.6 3.5 30 4 251.9 5.3 30 5 110.9 5.7 30 8 154.1 4.0 30 9 72.2 6.8 30 10 58.5 6.7 30 11 188.6 4.0 30 12 298.4 4.6 30 13 75.7 10.0 30 14 136.4 5.5 30 15 31.8 12.4 30 16 90.9 7.2 30 17 136.0 5.7 31 1 70.9 9.6 10 31 3 145.5 11.6 10 31 4 376.3 12.1 10 31 6 136.6 5.4 10 31 7 56.2 8.0 10 31 8 74.1 5.7 10 31 9 67.1 7.2 10 31 10 84.2 5.7 10 31 11 232.4 4.2 10 31 12 58.3 8.8 10 31 13 107.3 5.2 10 31 14 105.6 5.3 10 31 15 73 .3 8.1 10 31 16 100.7 6.1 10 32 0 105.2 6.5 10 32 1 271.7 5.9 10 32 2 29.5 9.6 10 32 3 100.3 6.1 10 32 4 104.0 5.5 10 32 5 69.5 7.6 10 32 6 33.2 12.3 10 32 7 13.2 6.5 10 32 8 123.8 3.8 10 32 9 123.4 4.9 10 32 10 187.6 4.0 10 32 11 110.3 6.3 10 32 12 124.4 4.0 10. 32 13 16.1 7.9 10 32 14 117.1 4.1 10 32 15 104.2 5.6 10 33 0 40.6 11.8 10 33 1 171.2 4.4 10 33 2 174.4 4.6 10 33 3 269.2 7.5 10 33 4 286.2 5.8 10 33 5 186.2 4.7 10 33 6 143.9 4.9 10 33 7 27.0 9.1 10 33 8 217.0 3.8 10 33 9 82.7 5.2 10 33 10 193.8 4.1 10 33 12 115.0 4.1 10 33 13 43.8 10.9 10 33 14 77.9 10.6 10 34 0 127.5 5.3 10 34 1 209.4' 4.6 10 34 2 83.5 6.4 10 34 3 79.5 6.1 10 34 4 231.7 5.5 10 34 5 89.5 6.6 10 34 6 59.8 6.2 10 34 7 141.4 3.8 10 34 8 99.1 5.5 10 34 9 95.7 6.3 10 34 10 61.3 7.0 10 34 11 99.3 5.6 10 34 12 135.9 4.1 10 35 0 143.4 5.1 10 35 1 73.1 7.3 10 35 2 96.6 5.9 10 35 3 54.3 9.8 10 35 4 132.3 3.5 10 35 5 80.8 6.4 10 35 6 27.4 10.2 10 35 7 198.1 5.0 10 35 8 42.2 13.0 10 35 9 40.2 10.9 10 35 10 67.9 5.8 10 35 11 22.2 11.1 10 36 0 56.6 8.3 10 36 1 68.4 7.3 10 36 2 67.6 6.0 10 36 3 94.5 5.4 10 36 4 113.7 5.1 10 36 5 179.6 4.7 10 36 6 108.7 4.5 10 36 8 92.1 5.4 10 37 0 219.5 5.2 10 37 1 166.3 5.1 10 37 2 45 .1 9.3 10 37 3 144.7 4.4 10 37 4 21 .1 9.9 10 37 5 56 .7 9.4 10 37 6 146.8 5.9 1 0 38 0 32.3 13.1 10 38 1 127.1 5.7 11 0 0 302.5 7.1 11 0 I 143.4 5.9 11 0 2 109.7 6.5 11 0 6 173.1 6.4 11 0 7 52.6 16.4 11 0 8 331.1 7.0 11 0 9 97.4 10.8 11 0 10 150.3 6.0 11 0 11 105.5 9.0 11 0 12 128.1 8.0 11 0 13 502.5 10.2 11 0 14 79.3 10.5 11 0 15 70.6 14.1 11 0 16 242.5 8.5 11 0 17 170.8 9.2 11 0 18 30.9 16.2 11 0 19 119.7 7.0 11 0 20 50.1 18.2 11 0 21 128.6 10.1 1 1 0 22 86.7 11.2 11 0 23 112.8 40.7 11 0 24 14.4 10.8 11 0 25 84.7 15.8 11 0 26 44.5 22.8 11 0 28 71.9 21.5 11F 1 0 430 .2 6.6 11 1 1 55 .5 16.1 11 1 2 545.7 7.4 11 1 6 141.4 6.5 11 1 7 57.3 11.3 11 1 8 483.8 8.3 11 1 9 220.4 4.7 11 1 10 94.3 6.5 11 1 11 127.8 6.6 11 1 12 168.4 4.6 11 1 13 28.6 11.5 11 1 14 167.0 4.3 11 1 15 17.2 8.7 11 1 16 27.0 12.2 11 1 17 218.2 4.3- 11 1 18 110.5 4.7 11 1 19 18.7 9.1 11 1 20 31.2 12.5 11 1 21 66.0 9.3 11 1 22 173.9 4.8 11 1 23 211.8 15.6 11 1 24 51.5 16.6 11 1 25 177.2 9.0 11 1 26 54.9 15.4 11 1 27 92.7 13.6 11 1 28 162.9 7.2 11 2 0 387.8 6.0 11 2 2 119.8 10.7 11 2 4 525.0 22.2 11 2 6 234.1 4.4 11 2 7 385.3 5.7 11 2 8 85.0 7.2 11 2 9 102.8 6.5 11 2 10 160.9 4.2 PCT/GB98/02542 1 2 11 188.0 4.7 1 2 12 178.2 4.3 1 2 13 350.4 6.1 1 2 14 78.8 1 2 15 214.9 4.1 1 2 16 32.8 14.2 1 2 17 67.0 8.9 1 2 18 85.4 6.6 1 2 19 125.0 1 2 20 230.9 6.6 1 2 21 113.2 5.4 1 2 22 206.7 1 2 23 276.1 11.5 1 2 24 116.3 1 2 25 87.4 11.4 1 2 26 71.1 13.1 1 2 27 84.6 16.8 1 2 28 149.7 7.8 1 3 0 189.1 4.2 1 3 1 29.6 13.9 1 3 2 343.5 10.2 1 3 5 142.0 11.4 1 3 6 202.2 1 3 7 263.8 5.1 1 3 8 21.6 10.4 1 3 9 381.0 5.9 1 3 10 202.3 1 3 11 179.2 4.3 1 3 12 206.5 1 3 13 184.9 1 3 14 146.9 4.4 1 3 15 148.9 1 3 16 32.9 14.0 1 3 17 271.4 4.4 1 3 18 142.0 5.8 1 3 19 100.4 1 3 20 101.3 5.8 1 3 21 72.2 8.6 1 3 22 298.9 1 3 23 358.3- 12.5 1 3 24 113.6 1 3 25 56.7 14.0 1 3 26 245.7 5.4 1 3 27 121.3 8.6 1 3 28 44.9 16.9 1 4 0 425.7 1 4 1 406.6 1 4 2 213.0 11.3 1 4 5 508.1 7.2 1 4 6 284.2 4.6 1 4 7 365.7 6.2 1 4 8 63.3 12.4 1 4 9 25.5 11.7 11 4 10 92.6 11 4 12 32.2 12.3 11 4 13 178.3 4.2 11 4 14 20.1 9.9 11 4 15 71.4 10.3 11 4 16 247.0 5.2 11 4 17 79.1 11 4 18 110.1 5.6 11 4 19 149.9 4.4 11 4 20 107.4 6.4 11 4 21 165.4 5.3 11 4 22 66.9 10.7 11 4 23 468.1 12.6 11 4 24 118.6 11.7 11 4 25 28.0 12.9 11 4 26 101.9 10.1 11 4 27 110.2 9.6 11 4 28 125.1 8.7 11 5 1 107.8 27.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -144- 2 410.8 21.0 5 211.5 5.0 6 104.3 5.7 7 273.8 5.8 8 685.6 9.6 9 364.5 6.3 10 213.3 4.4 11 141.6 4.5 12 51.4 13.9 13 232.4 4.8 14 277.5 4.6 15 203.8 4.3 16 159.7 4.2 17 58.4 9.2 18 26.6 11.5 19 133.3 5.4 20 70.7 8.6 21 86.1 7.5 22 142.5 5.5 23 315.2 12.6 24 36.3 14.5 25 210.4 5.3 26 162.5 5.7 27 93.3 9.4 28 74.9 15.8 6 0 835.4 28.0 6 1 289.7 18.4 6 4 312.3 4.8 6 5 134.8 4.5 6 6 735.7 11.1 6 7 81.0 11.4 6 8 481.8 6.6 6 9 120.3 6.1 6 10 219.2 4.3 6 11 108.0 5.8 6 12 39.3 12.1 6 13 183.3 4.0 6 14 49.9 9.9 6 15 104.1 5.2 6 16 136.4 6.7 6 17 203.9 4.1 6 18 189.1 3.9 6 19 200.7 4.5 6 20 153.0 4.9 6 21 183.3 4.9 6 22 89.1 9.3 6 24 92.3 8.7 6 25 40.4 15.2 6 26 207.9 6.7 6 27 54.3 15.5 6 28 26.3 12.9 -7 0 410.0 14.2 7 1 156.9 23.7 7 2 209.9 7.2 7 3 244.4 4.3 7 4 578.8 8.6 7 5 182.5 4.6 7 6 94.8 5.7 7 7 213.2 5.4 7 8 308.8 6.4 7 9 110.0 6.0 7 10 114.4 5.4 7 11 297.1 4.7 7 12 121.0 4.8 7 13 179.5 4.7 7 14 206.2 3.9 7 15 46.6 15.1 7 16 173.3 4.7 7 17 183.9 4.9 7 18 130.0 4.3 7 19 114.9 6.0 7 20 46.6 12.7 7 21 94.0 6.7 7 22 23.5 11.4 7 24 240.7 5.8 7 25 130.9 10.5 7 26 137.3 8.0 7 27 85.3 13.3 7 28 68.6 15.9 8 0 333.1 5.7 8 1 276.8 5.0 8 2 658.2 11.1 8 3 132.7 4.3 8 4 96.7 5.0 8 5 334.2 6.1 8 6 206.0 5.5 8 7 128.9 5.3 8 8 232.5 4.3 8 9 353.2 5.9 8 10 262.6 5.3 8 11 193.9 6.8 8 12 201.4 4.8 8 13 226.7 4.5 8 14 36.0 13.0 8 15 232.7 4.7 8 16 93.8 6.5 8 17 53.0 14.7 8 18 61.9 9.5 8 19 38.1 12.3 8 20 91.5 10.1 8 21 96.6 5.7 8 22 36.5 17.0 8 24 121.2 9.9 8 25 112.7 7.6 8 26 41.6 15.0 8 27 19.1 9.7 9 0 59.3 14.5 9 1 433.7 6.4 9 2 175.7 3.4 9 3 225.0 5.2 9 4 139.5 4.7 9 5 145.0 5.1 9 6 594.3 8.1 9 7 164.0 4.5 9 8 340.3 5.4 9 9 225.0 4.3 9 10 287.3 5.2 9 11 92.9 7.1 9 12 98.8 6.1 9 13 16.0 8.1 9 14 63.8 7.8 9 15 238.6 4.4 9 16 41.2 13.1 9 17 216.1 4.2 9 18 51.4 14.7 9 19 117.1 5.1 9 20 138.4 4.5 9 21 111.0 6.3 9 22 329.1 13.4 9 23 121.7 9.4 9 24 60.7 14.5 9 25 91.6 10.7 9 26 137.8 8.3 9 27 101.0 10.3 10 0 353.7 6.3 10 1 510.8 7.4 10 2 170.0 4.0 10 3 155.1 5.8 10 4 312.6 5.5 10 5 47.0 14.4 10 6 544.0 8.1 110 7 401.5 6.2 1 10 8 26.8 12.3 1 10 9 326.8 5.2 I1 10 10 251.0 4.3 11 10 11 215.4 4.1 11 10 12 339.3 5.7 11 10 13 111.3 4.8 11 10 14 208.3 3.9 11 10 15 153.2 3.9 11 10 16 106.7 5.0 11 10 17 199.2 4.0 11 10 18 115.4 12.4 11 10 19 164.4 4.7 11 10 20 213.2 4.3 11 10 21 24.5 11.7 11 10 22 272.3 11.2 11 10 23 130.8 7.6 11 10 24 29.0 13.4 11 10 25 106.1 7.7 11 10 26 37.8 16.8 11 10 27 27.2 12.9 11 11 0 284.1 5.3 11 11 1 158.3 3.5 11 11 2 496.5 10.7 11 11 3 90.3. 6.7 11 11 4 601.7 9.6 11 11 5 192.4 4.0 11 11 6 292.0 5.1 11 11 7 297.7 5.6 11 11 8 346.3 5.4 11 11 9 151.3 6.2 11 11 10 276.3 4.7 11 11 12 209.6 4.4 11 11 13 148.2 4.6 11 11 14 157.4 5.1 11 11 15 196.1 4.5 11 11 16 121.7 5.2 11 11 17 170.3 3.7 11 11 18 20.7 10.2 11 11 19 136.9 5.6 11 11 20 82.1 8.3 11 11 21 30.8 13.6 11 11 23 101.0 8.1 11 11 24 174.3 4.6 11 11 25 106.3 9.1 11 11 26 141.5 8.0 11 11 27 86.4 9.9 11 12 0 176.1 4.1 11 12 1 236.3 4.1 11 12 2 83.9 4.2 11 12 3 29.9 12.0 11 12 4 173.5 3.6 11 12 5 111.5 4.6 11 12 6 173.2 3.7 11 12 7 84.7 7.5 11 12 8 202.7 4.7 11 12 9 349.1 5.4 11 12 10 245.6 4.3 11 12 11 280.8 4.7 11 12 12 168.5 5.8 11 12 13 223.9 4.1 11 12 14 197.4 4.0 11 12 15 266.1 4.9 11 12 16 48.1 11.0 11 12 17 90.5 6.0 11 12 18 77.9 7.1 11 12 19 34.2 13.3 11 12 20 154.8 5.3 11 12 21 248.0 13.0 11 12 22 151.9 5.6 11 12 23 158.8 4.8 11 12 24 167.7 5.0 11 12 25 119.5 9.4 11 12 26 108.0 9.1 PCT/GB98/02542 1 13 0 363.7 6.4 1 13 1 107.1 7.1 1 13 2 163.5 1 13 3 298.7 5.1 1 13 4 80.5 6.3 1 13 5 389.7 6.1 1 13 6 146.2 3.8 1 13 7 192.3 4.4 1 13 8 249.3 5.2 1 13 9 305.1 4.6 1 13 10 126.2 4.7 1 13 11 134.9 4.2 1 13 12 69.1 6.9 1 13 13 299.6 11 13 14 1.80.7 1 3.9 11 13 15 18.0 8.7 1I 13 16 61.5 8.1 [1 13 17 148.7 11 13 18 170.9 11 13 19 118.8 11 13 20 36.9 12.9 11 13 21 315.2 15.2- 11 13 22 173.3 4.8 11 13 23 31.5 13.1 11 13 24 85.6 11.2 11 13 25 23.9 11.7 11 13 26 19.4 9.7 11 14 0 530.8 11 14 1 350.7 6.1 11 14 2 244.7 4.2 11 14 3 146.1 6.2 11 14 4 227.0 3.8 11 14 5 261.1 11 14 6 233.2 4.4 11 14 7 52.9 11.2 1 1 14 8 230.4 3.9 11 14 9 245.8 4.9 11 14 10 76.6 7.6 11 14 11 156.3 11 14 12 165.9 4.9 11 14 13 166.5 4.1 11 14 14 221.6 3.9 11 14 15 141.9 5.2 11 14 16 59.2 9.7 11 14 17 151.9 4.3 11 14 18 60.4 9.7 11 14 19 181.0 11 14 20 130.3 11.3 11 14 21 135.8 7.7 11 14 22 116.6 6.2 11 14 23 116.9 6.9 11 14 24 152.6 6.4 11 14 25 87.8 10.3 11 14 26 110.1 7.9 11 15 0 174.9 3.7 11 15 1 139.6 5.7 11 15 2 244.1 11 15 3 149.7 4.2 11 15 4 452.8 8.9 11 15 5 217.1 4.1 11 15 6 326.6 5.1 11 15 7 108.5 4.7 1l 15 8 183.2 4.1 11 15 9 86.0 5.9 11 15 10 153.9 4.2 11 15 11 162.8 3.6 i 1 15 12 126.7 11 15 13 164.9 3.9 11 15 14 133.8 4.4 11 15 15 32.7 12.1 11 15 16 109.1 5.2 11 15 17 65.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -145- 1 15 18 94.4 8.2 1 15 19 145.6 4.7 1 15 20 357.9 12.3 1 15 21 85.8 8.6 1 15 22 65.2 10.5 1 15 23 91.5 8.0 1 15 24 21.9 10.8 1 I5 25 35.4 15.0 1 15 26 74.6 18.6 1 16 0 250.2 4.0 1 16 1 418.5 6.7 1 16 2 238.5 3.8 1 16 3 173.8 3.7 1 16 4 339.4 4.9 1 16 5 298.0 5.1.

1 16 6 227.9 3.8 1 16 7 106.3 5.6 1 16 8 226.3 4.1 1 16 9 127.4 4.6 1 16 10 317.1 4.9 1 16 11 237.2 4.0 1 16 12 251.6 4.2 1 16 13 102.2 6.5 1 16 14 125.7 4.4 1 16 15 61.0 7.1 1 16 16 139.1 4.8 1 16 17 247.3 4.7 1 16 18 127.5 7.1 1 16 19 189.1 6.9 1 16 21 152.1 6.9 1 16 22 123.7 7.2 1 16 23 186.1 6.4 1 16 24 149.7 6.4 1 16 25 211.7 6.2 1 17 0 531.0 7.2 1 17 1 27.7 11.1 1 17 2 385.3 6.7 1 17 3 209.1 3.7 1 17 4 127.8 4.2 1 17 5 131.7 4.5 1 17 6 76.8 5.8 1 17 7 143.1 4.1 1 17 8 212.1 3.7 1 17 9 196.5 3.7 1 17 10 68.0 6.7 1 17 11 187.2 3.7 1 17 12 113.7 4.7 1 17 13 18.0 8.9 1 17 14 84.8 6.5 1 17 15 153.3 5.3 .1 17 16 94.0 5.9 1 .17 17 21.1 10.1 [1 17 18 108.0 4.9 1 17 19 398.5 11.4 11 17 20 21.1 10.7 11 17 21 122.0 6.8 I1 17 22 128.7 6.6 11 17 23 158.3 6.3 11 17 24 123.2 6.6 11 17 25 123.7 8.1 11 18 0 132.8 3.8 11 18 1 310.8 4.8 11 18 2 73.7 5.7 11 18 3 185.1 3.9 11 18 4 483.3 8.1 11 18 5 223.4 4.4 11 18 6 94.8 4.6 11 18 7 179.3 3.6 11 18 8 67.3 5.7 11 18 9 170.3 4.3 11 18 10 36.8 14.4 11 18 11 51.5 7.8 11 18 12 154.9 4.2 11 18 13 77.8 6.5 11 18 14 95.8 5.9 11 18 15 124.8 5.4 11 18 16 156.1 3.8 11 18 17 23.7 11.4 11 18 18 95.9 10.9 11 18 19 113.0 5.5 11 18 20 40.4 13.9 11 18 21 1 97.3 5.0 11 18 22 138.6 7.9 11 18 23 164.5 5.4 11 18 24 64.6 16.6 11 19 0 112.5 5.2 11 19 1 76.0 4.2 11 19 2 259.7 4.8 11 19 3 284.3 5.0 11 19 4 206.7 4.0 11 19 5 239.1 3.8 11 19 6 130.6 3.7 11 19 7 124.5 3.7 11 19 8 60.2 10.0 11 19 9 190.5 3.6 11 19 10 30.6 12.1 11 19 11 113.9 4.9 11 19 12 17.2 8.5 11 19 13 38.5 11.8 11 19 14 107.8 5.2 11 19 15 81.4 6.0 11 19 16 162.4 4.6 11 19 17 17.7 8.7 11 19 18 275.2 12.3 11 19 19 20.3 10.2 11 19 20 210.4 5.6 11 19 21 122.1 6.1 11 19 22 43.7 13.9 11 19 23 122.1 6.4 11 19 24 44.0 17.1 11 20 0 364.1 5.6 11 20 1 139.7 3.8 11 20 2 174.0 3.8 11 20 3 92.2 3.2 11 20 4 116.7 3.9 11 20 5 59.8 5.1 11 20 6 67.1 6.2 11 20 7 133.5 5.0 11 20 8 154.8 3.6 11 20 9 215.2 3.6 11 20 10 246.4 4.2 11 20 11 114.7 4.4 11 20 12 108.2 4.9 11 20 13 96.5 4.4 11 20 14 105.6 4.8 11 20 15 73.1 7.4 11 20 16 31.6 11.5 11 20 17 290.5 22.6 11 20 18 90.0 8.3 11 20 19 171.3 4.7 11 20 20 168.1 5.0 11 20 21 201.2 6.1 11 20 23 60.2 15.8 11 21 0 220.4 4.2 11 21 1 200.0 3.9 11 21 2 183.7 3.8 11 21 3 137.6 5.0 11 21 4 165.5 6.4 11 21 5 121.1 4.1 11 21 6 82.4 5.1 11 21 7 264.8 4.3 11 21 8 314.6 4.6 11 21 9 136.6 4.6 11 21 10 141.7 4.5 11 21 11 194.9 4.4 11 21 12 233.1 4.0 11 21 13 138.6 4.7 11 21 14 72.7 7.0 11 21 15 213.8 4.1 11 21 16 50.8 19.7 11 21 17 102.4 8.8 11 21 18 189.0 4.7 11 21 19 78.5 10.1 11 21 20 24.8 11.3 I 1 21 21 110.4 9.8 11 21 22 141.0 5.2 11 21 23 34.1 13.2 11 22 0 240.0 5.0 11 22 1 171.5 4.7 11 22 2 62.0 6.1 11 22 3 281.4 4.5 11 22 4 232.8 3.8 11 22 5 99.8 4.1 11 22 6 113.0 4.0 11 22 7 166.5 3.7 11 22 8 170.8 3.4 11 22 9 41.5 12.3 11 22 10 27.2 10.5 11 22 11 106.3 5.6 11 22 12 92.8 6.0 11 22 13 24.7 10.7 11 22 14 65.5 7.0 11 22 15 82.6 7.5 11 22 16 20.1 9.8 11 22 17 74.4 8.6 11 22 18 152.9 4.9 11 22 19 148.7 5.4 11 22 20 128.4 8.1 11 22 21 20.1 9.9 11 22 22 88.2 8.5 11 23 0 176.5 3.1 11 23 1 101.0 4.0 11 23 2 72.4 4.9 11 23 3 273.9 5.0 11 23 4 127.7 4.6 11 23 5 208.4 4.0 11 23 6 94.0 4.7 It 23 7 64.4 7.1 11 23 8 252.0 4.1 11 23 9 107.4 4.2 11 23 10 45.8 9.4 11 23 11 120.1 4.0 11 23 12 80.7 6.6 11 23 13 135.6 4.1 11 23 14 148.3 4.9 11 23 15 112.6 26.6 11 23 16 144.3 4.8 11 23 17 69.6 8.1 11 23 18 133.9 5.8 11 23 19 145.6 6.8 11 23 20 19.6 9.7 11 23 21 55.5 14.4 11 23 22 88.6 9.5 It 24 0 214.5 3.6 11 24 1 100.8 3.8 11 24 2 101.5 4.1 11 24 3 223.1 3.9 11 24 4 17.0 7.7 11 24 5 225.4 3.6 11 24 6 115.3 4.9 11 24 7 216.4 3.6 11 24 8 108.7 6.0 11 24 9 25.1 10.6 11 24 10 99.4 4.2 11 24 11 96.8 6.7 11 24 12 29.6 12.1 11 24 14 119.2 22.5 11 24 15 24.2 11.2 11 24 16 19.7 11 24 17 81.3 10.1 11 24 18 140.8 5.3 11 24 19 167.8 5.2 11 24 20 81.7 9.7 11 24 21 121.2 11 25 0 158.6 4.8 11 25 1 219.6 4. 3 11 25 2 135.6 11 25 3 309.6 6.1 11 25 4 113.0 3.7 11 25 5 140.8 11 25 6 79.2 6.4 11 25 7 135.2 3. 3 11 25 8 73.7 11 25 9 160.0 4.1 11 25 10 137.7 4.6 11 25 11 103.9 4.6 11 25 12 154.9 11.8 11 25 13 246.5 13.8 11 25 14 181.8 4.7 11 25 15 43.5 14.0 11 25 16 171.8 5.3 11 25 17 123.4 6.6 11 25 18 152.1 5.9 11 25 19 93.7 10.3 11 25 20 124.7 11 26 0 138.9 4.9 11 26 1 135.8 2.9 11 26 2 84.0 3.6 11 26 3 172.8 11 26 4 189.7 4.9 11 26 5 96.9 4.2 11 26 6 20.4 9.7 11 26 7 135.7 11 26 8 106.2 4.9 11 26 9 32.8 10.9 11 26 10 127.6 4.6 11 26 12 203.4 6.9 11 26 13 57.9 11 26 14 212.4 4.4 11 26 15 98.5- 11 26 16 129.1 5.6 11 26 17 259.2 5.7 11 26 18 144.2 6.1 11 26 19 72.1 11 26 20 29:3 14.7 11 27 0 349.2 5.7 11 27 1 163.3 4.2 11 27 2 112.3 3.2 11 27 3 245.6 4.6 11 27 4 185.1 3.9 11 27 5 74.3 11 27 6 135.1 5.1 11 27 7 106.4 11 27 8 176.3 4.2 11 27 9 130.2 6.6 11 27 12 22.0 10.4 11 27 13 23.7 11.0 11 27 14 90.3 7.4 11 27 15 42.7 13.0 11 27 16 44.4 11.7 11 27 17 21.3 10.2 11 27 18 96.4 7.1 11 27 19 27.6 12.9 11 28 0 286.0 5.9 11 28 1 108.4 6.1 11 28 2 79.1 11 28 3 171.6 3.6 11 28 4 185.5 4.3 SUBSTITUTE SHEET (RULE 26) WO 99/1 0379 -146- 1 1 28 5 77.5 4.7 11 28 6 278.6 6.4 11 28 7 19.2 8.9 11 28 9 56.5 12.5 11 28 10 25.3 10.9 11 28 11 90.5 5.1 11 28 12 215.9 4.1 11 28 13 59.5 12.1 11 28 14 156.1 4.2 11 28 15 40.0 12.2 11 28 16 123.1 5.9 11 28 17 34.7 13.1 11 28 18 49.0 15.8 11 29 0 29.5 12.3 11 29 1 60.2 6.9 11 29 2 73.9 11.0 11 29 3 17.0 8.1 11 29 4 250.7 4.8 11 29 5 150.2 13.0 11 29 7 21.2 10.2 11 29 8 79.8 7.3 11 29 9 170.5 3.9 11 29 10 117.4 4.1 11 29 11 113.5 4.5 11 29 12 161.6 4.0 11 29 13 116.7 6.2 11 29 14 156.3 4.9 11 29 15 94.0 7.2 11 29 16 88.9 6.7 11 29 17 123.7 6.1 11 30 1 262.2 8.4 11 30 4 12.3 6.2 11 30 5 145.0 3.7 11 30 6 84.2 7.6 11 30 7 180.7 4.2 11 30 8 14.4 7.1 11 30 9 52.8 10.6 11 30 10 100.9 5.7 11 30 11 54.5 10.9 11 30 12 253.5 4.5 11 30 13 96.4 7.6 11 30 14 54.7 9.8 11 30 15 24.6 12.0 11 30 16 69.2 8.7 11 31 0. 31.1- 12.6 11 31 1 84.0 4.9 11 31 2 41.8 10.3 11 31 3 151.7 3.4 11 31 4 79.7 5.4 11 31 5 57.1 7.2 11 31 6 145.1 5.1 11 ;31 7 96.1 4.7 11 31 8 60.9 9.4 11 31 9 63.7 8.3 11 31 10 205.2 3.9 11 31 11 154.2 4.4 11 31 12 167.4 4.1 11 31 13 184.1 4.8 11 31 14 126.6 4.8 11 31 15 55.6 12.5 11 32 0 103.0 5.9 11 32 1 221.1 5.9 11 32 2 109.1 3.5 11 32 3 109.8 3.5 11 32 4 74.8 5.0 11 32 5 50.1 7.2 11 32 6 95.3 4.3 11 32 7 63.3 8.0 11 32 8 102.6 5.3 11 32 9 94.2 5.8 11 32 10 133.4 6.9 11 32 11 87.7 6.4 11 32 12 127.7 5.3 11 32 13 46.7 11.7 11 33 0 46.4 13.2 11 33 1 90.0 10.0 11 33 2 152.7 5.1 11 33 3 260.7 4.5 11 33 4 128.5 4.4 11 33 5 118.4 3.5 11 33 6 47.3 10.2 11 33 7 227.7 5.9 11 33 8 56.5 10.7 11 33 9 199.6 4.1 11 33 10 72.2 7.4 11 33 11 101.2 4.6 11 33 12 67.0 8.5 11 34 0 176.9 5.2 11 34 1 120.1 5.5 11 34 2 137.2 6.2 11 34 3 69.4 5.5 11 34 4 137.4 4.1 11 34 5 103.3 4.2 11 34 6 25.5 10.0 11 34 7 78.5 8.0 11 34 8 65.1 7.9 11 34 9 25.2 1-1.6 11 34 10 21.4 10.2 11 35 0 113.6 5.9 11 35 1 111.0 5.3 11 35 2- 84.8 6.4 11 35 3 114.4 5.4 11 35 4 17.9 8.8 11 35 5 74.1 5.4 11 35 6 68.1 4.7 11 35 7 66.6 9.5 11 35 8 83.9 11.6 11 36 0 189.9 4.9 11 36 1 190.2 4.6 11 36 2 154.3 5.0 11 36 3 55.1 10.4 11 36 4 84.7 6.6 11 36 5 107.3 4.8 12 0 0 86.6 23.5 12 0 I 202.8 9.4 12 0 2 254.2 10.0 12 0 3 466.1 9.2 12 0 4 212.2 6.9 12 0 5 13.9 10.3 12 0 6 211.5 5.8 12 0 7 68.2 16.4 12 0 8 77.7 10.5 12 0 9 76.0 11.1 12 0 10 531.4 10.1 12 0 11 83.5 10.9 12 0 12 147.8 6.6 12 0 13 23.2 15.7 12 0 14 83.9 11.9 12 0 15 154.2 6.3 12 0 16 93.4 12.3 12 0 17 81.9 10.5 12 0 18 147.0 6.0 12 0 19 81.9 16.3 12 0 20 22.0 15.4 12 0 21 27.1 17.8 12 0 22 247.8 14.3 12 0 23 43.4 19.4 12 0 24 76.3 19.0 12 0 25 167.8 8.9 12 0 26 36.5 23.0 12 0 27 163.3 10.6 12 1 0 71.9 17.1 12 I I 124.9 9.5 12 1 2 266.2 4.9 1 3 246.9 4.3 1 4 74.5 8.8 1 5 173.9 5.3 1 6 304.0 5.2 1 7 94.6 8.1 1 8 78.2 7.3 I 9 135.6 5.5 1 10 79.6 8.3 1 11 163.0 4.2 1 12 213.6 4.2 1 13 100.3 7.7 1 14 89.0 8.1 1 I5 231.2 4.4 1 16 102.3 7.3 1 17 63.4 13.0 1 18 193.7 5.0 1 19 66.4 10.0 I 20 188.3 5.7 1 21 200.7 6.7 1 22 274.9 15.8 1 23 46.7 14.3 1 24 94.2 9.1 1 25 111.4 9.7 1 26 140.0 10.4 1 27 105.2 9.6 2 0 200.6 6.5 2 1 699.3 13.2 2 2 162.6 10.0 2 3 658.2 9.5 2 4 138.3 5.4 2 5 232.3 4.3 2 6 451.5 7.3 2 7 117.2 5.7 2 8 346.6 5.4 2 9 47.1 11.4 2 10 188.4 4.6 2 11 282.9 5.0 2 12 275.4 4.9 2 13 123.9 6.5 2 14 114.1 5.5 2 15 106.3 6.8 2 16 27.0 11.9 2 17 130.6 8.7 2 18 108.3 5.5 2 19 68.2 9.1 2 20 26.0 12.0 .2 21 120.6 6.4 2 22 305.5 17.1 2 23 118.3 6.1 2 24 53.1 14.6 2 25 128.0 8.0 2 26 71.5 14.8 2 27 25.3 12.3 3 0 468.2 12.8 3 1 220.5 5.5 3 2 280.5 6.8 3 3 407.3 6.8 3 4 265.2 5.4 3 5 188.6 4.8 3 6 368.3 6.2 3 7 404.7 5.9 3 8 94.4 6.7 3 9 90.6 5.9 3 10 20.4 9.8 3 11 155.9 4.8 3 12 92.8 5.7 3 13 55.5 14.6 3 14 171.7 5.1 3 15 79.7 7.8 3 16 112.0 6.6 3 17 29.8 12.7 3 18 144.8 4.9 PCT/GB98/02542 2 3 19 191.6 .2 3 20 86.1 7.8 .2 3 21 88.3 12 3 22 261.3 15.8 .2 3 23 100.0 7.2 S2 3 24 45.6 15.5 12 3 25 168.5 2 3 26 76.7 15.7 [2 3 27 24.7 12.3 12 4 0 514.5 12 4 1 368.4 5.6 2 4 2 121.8 5.1 12 4 3 247.9 5.2 [2 4 4 181.2 4.7 12 4 5 59.0 10.6 12 4 6 201.4 4.6 12 4 7 101.5 5.6 12 4 8 174.5 4.3 12 4 10 23.0 10.5 12 4 11 48.6 11.5 12 4 12 45.6 1 3.2 12 4 13 36.1 13.9 12 4 14 155.4 4.2 12 4 15 96.9 12 4 16 201.5 4.1 12 4 17 151.3 5.4 12 4 18 104.6 5.4 12 4 19 118.1 6.3 12 4 20 117.0 12 4 21 214.6 12 4 22 38.5 18.1 12 4 23 78.9 9.2 12 4 24 43.2 15.8 12 4 25 130.4 7.4 12 4 26 117.7 13.5 12 4 27 90.9 10.5 12 5 0 146.3 4.2 12 5 1 204.4 4.6 12 5 2 201.8 5.1 12 5 3 234.6 5.2 12 5 4 196.9 4.3 12 5 5 198.4 4.4 12 5 6 250.9 4.7 12 5 7 230.4 4.2 12 5 8 271.3 4.6 12 5 9 160.0 4.8 12 5 10 251.1 4.3 12 5 11 105.3 6.3 12 5 12 154.2 4.3 12 5 13 335.4 5.7 12 5 14 163.8 12 5 15 389.9 12 5 16 32.2 12.7 12 5 17 194.3 12 5 18 46.5 12.1 12 5 19 95.0 6.6 12 5 20 76.2 9.1 12 5 21 167.7 6.9 12 5 22 24.6 12.1 12 5 23 26.1 12.2 12 5 24 64.6 14.8 12 5 25 109.4 12 5 26 110.5 9.4 12 6 0 307.5 12 6 1 363.9 5.7 12 6 2 130.5 4.9 12 6 3 533.3 10.2 12 6 4 412.4 6.8 12 6 5 208.1 4.1 12 6 6 73.0 6.7 12 6 7 108.8 5.2 12 6 8 117.7 7.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -147- 181.3 4.0 353.2 5.2 152.8 4.8 152.8 4.2 82.2 6.2 114.0 6.0 97.6 7.3 206.2 5.1 35.9 13.6 111.1 7.0 154.4 5.3 100.0 13.1 92.9 23.8 28.2 12.9 100.5 7.1 165.1 6.3 41.9 16.5 49.8 19.0 118.9 14.3 330.9 5.0 264.8 4.3 172.6 5.2 237.1 4.9 338.3 6.5 128.0 5.3 232.9 4.3 177.8 5.2 114.1 5.3 62.0 9.0 146.1 5.5 66.8 7.9 141.1 4.3 144.3 4.7 46.5 15.2 152.8 5.1 73.8 9.4 133.8 5.4 152.8 5.1 36.6 12.7 28.7 12.8 191.5 16.6 *103.2 7.9 180.0 5.6 *102.8 8.0 71.8 11.8 51.8 17.3 482.5 7.2 140.7 3.7 65.0 5.4 219.2 6.4 61.2 13.0 185.8 4.1 222.9 5.0 17.8 8.8 241.9 5.0 149.3 4.6 )375.9 5.9 1 232.7 4.4 Z 321.5 5.0 3 60.2 12.8 4 161.6 6.6 125.4 6.3 6 60.6 11.8 7 47.7 13.9 8 89.2 7.3 9 28.7 12.4 0 19.9 9.7 1 404.0 12.4 2 63.6 10.6 3 76.3 9.6 4 54.9 15.9 33.4 14.5 12 8 12 9 12 9 12 S 12 S 12 S 12 S 12 S 12 S 12 S 12 S 12 S 12 S 12 S 129 12 S 12 129 129 129 12 12 12 12 12 12 12 12 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 1 12 12 121 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 26 171.7 8.5 0 368.8 6.4 1 373.4 6.1 2 413.2 6.8 3 218.0 4.6 4 220.4 4.5 5 268.3 4.7 6 157.9 4.6 7 584.8 8.5 8 55.9 8.9 9 129.5 6.1 10 131.8 4.2 11 165.1 4.7 12 109.4 6.1 13 104.2 6.2 14 21.5 9.7 15 187.8 4.3 16 15.1 7.6 17 125.0 6.0 18 56.2 11.5 19 31.6 12.8 20 134.0 5.6 21 121.1 15.6 22 83.9 8.0 23 102.1 10.7 24 178.4 5.9 25 78.5 13.0 26 160.4 8.1 0 581.2 10.1 1 266.2 5.5 2 78.1 6.8 3 198.2 6.1 4 66.9 8.9 5 165.2 4.0 6 125.8 5.6 7 164.8 4.1 P8 241.8 4.2 9 107.6 7.0 10 201.0 4.8 11 378.0 5.4 I12 26.8 11.9 1 13 141.2 4.2 14 159.4 3.8 I15 176.4 4.6 16 68.9 8.8 17 33.0 13.4 18 135.9 6.0 19 97.4 7.6 21 27.2 12.4 22 133.1 5.6 )23 104.1 8.2 )24 85.8 10.5 )25 44.4 17.8 )26 101.4 8.2 1 0 203.4 5.4 1 1 286.5 8.3 1 2 238.3 4.5 1 3 142.6 6.5 1 4 233.3 4.9 1 5 24.8 11.2 1 6 83.0 6.2 1 7 360.8 5.1 1 8 62.5 8.4 1 9 168.8 4.0 1 10 162.5 4.0 1 11 80.5 6.7 1 12 266.5 4.8 1 13 158.5 5.1 1 14 78.3 7.2 1 15 118.5 4.9 1 16 150.2 4.5 1 17 70.8 9.1 38.6 13.7 71.9 17.9 328.5 9.2 191.4 7.4 84.0 9.5 144.5 7.9 19.0 9.7 43.0 17.8 55.9 16.0 93.5 4.9 182.0 3.6 229.7 3.9 312.8 4.8 362.9 5.3 134.5 4.1 296.7 4.7 161.5 4.4 270.2 4.8 115.9 4.3 199.2 4.0 37.4 12.1 164.7 4.6 119.7 4.9 229.3 4.0 28.3 11.7 157.1 5.3 153.3 5.4 48.9 13.0 166.5 4.8 226.1 17.9 193.2 5.1 25.6 12.7 82.4 10.4 163.0 7.5 58.1 15.0 250.8 4.6 395.6 6.7 126.4 4.4 303.9 4.6 309.9 4.5 243.5 4.4 585.6 8.6 91.6 4.8 264.5 4.4 67.0 6.4 I18.5 9.2 51.2 10.5 t184.5 3.9 1 190.5 4.4 1 18.9 9.3 i27.4 11.6 i199.4 4.8 1 65.7 8.8 193.4 6.7 S122.0 23.7 1 242.0 4.6 Z 145.7 6.5 3 111.7 7.7 4. 89.6 10.6 5 30.0 13.2 I107.0 5.3 211.3 5.0 t134.2 4.1 1204.8 3.7 1116.6 4.2 i235.2 4.3 i121.2 5.4 1 99.9 4.9 128.7 4.3 )69.0 6.7 0 28.9 11.2 1 239.4 4.1 12 14 1: 12 14 1 12 14 11 12 14 1.

12 14 11 12 14 1* 12 14 1.

12 14 I' 12 14 2' 12 14 2 12 14 2 12 14 2 12 14 2 12 14 2 12 15 12 15 1 12 15 12 15 12 15 12 15 12 15 12 15 12 15 1 12 15 1 12 15 1 12 15 1 12 15 1 12 15 1 12 15 1 12 15 1 12 15 1 12 15 1 12 15 2 12 15 2 12 152 12 152 12 152 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 16 12 17 12 17 12 17 12 17 12 17 12 17 12 17 12 17 12 17 12 17 111.L6 7.6 110.3 258.7 4.2 98.7 48.4 13.1 184.5 40.2 12.8 385.4 12.6 259.6 157.4 5.6 75.1 10.5 22.2 11.0 52.4 15.3 23.8 11.5 145.0 6.4 334.3 5.2 171.1 6.2 283.5 273.3 6.4 233.2 4.1 113.3 4.3 68.7 7.8 65.2 210.2 4.3 91.4 4.9 112.3 5.4 190.1 60.4 65.8 7.8 215.0 4.4 56.8 14.0 P115.9 12.2 172.4 155.0 144.3 6.8 55.6 15.2 28.7 13.2 36.8 12.8 175.3 3.7 101.7 3.9 100.9 3.9 126.8 4.2 85.7 190.5 3.8 190.1 3.8 101.5 259.0 4.6 )117.7 5.2 1 32.7 11.5 2 148.6 4.3 3 22.6 10.2 4 36.9 11.9 5 114.5 5 91.2 7 54.9 10.3 8 350.7 11.6 9 72.9 0 138.1 5.7 1 41.1 15.6 2 45.6 13.9 3 148.7 11.9 4 138.3 6.9 )210.8 6.9 1 229.1 4.4 Z 122.5 4.6 3156.9 3.9 188.2 5 85.4 5.3 5 183.2 3.6 7 204.1 3.9 8 201.4 3.9 9 162.3 3.8 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -148- 158.9 3.8 64.7 7.0 95.1 5.3 56.3 11.8 139.9 6.2 18.9 9.2 95.0 7. 3 36.6 15 .7 17.5 8.8 20.7 10.4 113.1 7.6 74.4 10.7 37.9 15.2 30.1 13.9 67.3 17.6 23.4 9.8 137.6 4.1 33.4 10.4 131.4 3.7 203.4 5.9 44.7 10.9 249.1 4.2 125.4 4.0 130.3 4.4 58.9 8.0 202.8 3.8 147.9 4.6 150.6 4.5 142.3 4.9 122.8 5.5 25.6 11.7 25.3 11.8 268.2 20.2 28.4 12.0 31.7 12.7 66.8 14.4 168.3 5.6 27.0 13.2 19.2 9.7 62.0 10.3 205.0 4.1 126.9 4.0 202.3 4.1 159.9 4.6 63.4 7.4 25.4 11.0 144.1 3.6 38.2 11.9 176.4 3.6 204.6 4.2 79.5 5.6 53.8 10.0 92.7 5.5 72.5 8.3 132.8 5.5 258.0 10.3 19.5 9.9 36.5 13.9 90.3 7.6 37.5 13.7 28.3 12.9 111.1 6.8 1 23.5 11.7 170.3 3.7 72.3 5.1 40.0 9.6 259.2 4.8 233.2 3.9 23.1 10.4 161.7 3.7 60.3 6.8 116.2 5.0 96.9 6.1 14.4 7.3 96.5 7.1 115.0 5.9 74.2 7.3 163.6 13.0 140.2 6.7 129.0 5.3 19.1 9.4 74.8 11.6 50.2 13.8 63.4 11.4 70.0 13.3 156.6 3.8 118.8 3.8 161.9 4.1 226.8 3.9 164.9 5.0 47.4 10.8 103.1 4.4 228.9 4.0 95.8 5.2 89.8 5.3 108.1 4.9 120.8 5.6 128.7 4.9 22.9 11.6 102.4 13.3 30.5 12.3 40.2 14.3 163.3 5.2 171.1 5.9 75.7 10.9 121.6 7.1 57.8 22.9 149.4 5.1 152.0 3.9 79.8 5.4 145.8 3.8 150.0 3.1 116.1 3.7 211.1 3.6 139.9 3.7 178.6 3.7 219.7 3.8 F126.3 4.6 98.8 4.8 135.1 5.0 114.7 8.1 228.3 9.6 19.1 9.2 128.8 5.5 186.5 5.1 77.4 11.3 18.2 9.1 133.0 5.8 1 42.0 14.1 115.8 3.2 125.5 3.2 57.8 5.9 135.4 3.4 120.3 5.5 88.5 4.2 75.1 5.8 86.4 4.7 35.2 11.3 F101.3 4.8 3 116.0 4.3 1 48.8 13.3 2 45.0 15.0 3 215.7 21.4 4 239.6 4.3 128.8 6.0 97.5 6.9 132.9 5.0 128.3 5.2 31.9 13.7 74.5 12.1 185.1 4.8 192.2 5.2 116.7 4.1 165.8 3.7 162.0 3.9 93.6 4.8 52.7 8.4 94.5 5.2 312.0 5.3 62.4 7.8 87.8 5.9 88.9 23.8 20.8 10.2 62.1 10.0 88.4 7.1 137.3 5.0 112.6 6.0 67.7 10.8 173.1 5.3 161.0 6.3 70.3 13.6 90.5 8.0 19.1 9.5 65.8 5.0 32.3 9.4 15.6 7.4 241.6 4.5 214.4 4.4 207.7 4.1 131.2 5.0 16.4 8.3 277.0 18.0 15.0 7.6 112.0 5.2 239.6 4.6 207.1 6.7 79.7 8.8 197.9 4.5 34.2 12.4 22.9 11.1 168.8 7.9 118.4 6.4 141.6 3.8 192.3 5.5 145.2 7.5 222.4 5.4 59.5 7.1 44.6 13.7 178.3 14.0 188.1 17.7 127.7 5.1 1 39.1 12.4 Z40.5 12.4 ;54.5 12.2 t 73.8 8.6 5 126.7 6.7 5 96.0 6.6 7 189.2 4.8 3 124.6 5.8 I238.0 4.0 395.6 5.8 65.9 5.3 95.0 4.7 163.2 4.3 33.7 14.0 193.6 9.5 8 57.5 11.4 9 167.9 4.3 10 117.8 4.3 11 145.0 4.4 12 103.8 13 82.8 7.9 14 70.5 8.4 15 239.2 4.9 16 52.6 11.8 17 57.2 11.9 0 80.2 16.1 2 81.5 7.4 3 160.4 12.1 4 192.6 8.4 5 105.2 20.9 6 144.6 5.6 7 34.9 12.4 8 225.2 4.4 9 98.0 10 129.5 4.8 11 184.8 4.3 12 182.9 5.3 13 75.3 8.8 14 118.7 15 132.5 5.7 16 55.9 12.1 0 174.5 5.2 1 192.8 6.7 2 121.5 3 128.2 4.2 4 108.2 3.4 5 71.6 5.2 6 101.8 4.1 7 59.8 8 75.0 8.2 9 34.3 12.8 10 104.5 5.1 11 212.1 4.9 12 27.3 12.8 13 48.2 15.3 14 93.8 6.2 15 107.7 0 67.0 1 182.0 5.6 2 96.5 3 18.2 4 27.9 11.0 5 100.8 4.8 6 89.9 10.7 7 133.4 4.8 8 147.5 4.2 9 157.7 5.2 10 161.3 5.8 11 26.3 12.1 12 34.4 12.8 13 48.3 13.0 14 95.3 6.1 0 104.1 1 98.9 2 36.1 12.6 3 114.6 4.2 4 82.7 7.9 5 81.7 7.9 6 139.0 5.3 7 144.6 5.1 8 77.9 9 70.6 6.6 10 87.3 11 100.4 12 31.8 11.8 13 77.7 7.8 0 220.7 7.3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -149- 12 32 1 50.7 9.3 12 32 2 111.6 5.1 12 32 3 132.4 9.6 12 32 4 97.3 7.4 12 32 5 111.7 3.8 12 32 6 93.1 4.6 12 32 7 90.7 4.7 12 32 8 90.6 7.1 12 329 112.0 5.5 12 32 10 70.6 6.6 12 32 11 83.0 6.8 12 33 0 76.0 5.6 12 33 1 149.2 5.6 12 33 2 90.4 5.0 12 33 3 169.6 3.9.

12 33 4 146.3 7.9 12 33 5 50.6 16.4 12 33 6 23.0 10.8 12 33 7 113.3 5.4 12 33 8 64.1 8.5 12 33 9 100.6 6.8 12 34 0 48.1 13.4 12 34 1 114.4 7.9 12 34 2 77.9 8.4 12 34 3 33.4 11.9 12 34 4 121.8 6.0 12 34 5 73.6 7.6 12 34 6 107.2 9.4 12 34 7 13.6 6.9 12 35 0 182.4 5.2 12 35 1 36.9 13.0 12 35 2 122.8 5.5 12 35 3 21.9 10.2 12 35 4 53.8 8.0 13 0 0 456.7 9.7 13 0 1 378.7 7.8 13 0 2 265.8 9.4 13 0 3 100.0 17.5 13 0 4 39.5 19.7 13 0 5 192.1 5.7 13 0 6 67.0 17.2 13 0 7 48.6 21.0 13 0 8 243.7 6.3 13 0 9 63.7 14.6 13 0 10 47.8 21.2 13 0 11 73.0 14.2 13 0 12 204.3 6.6 13 0 13 172.4 6.3 13 0 14 89.8 9.1 13 0 15 45.9 20.7 13 0 16 149.3 6.4 13 -0 17 121.8 7.4 13 0 18 74.0 18.7 13 0 19 36.9 24.2 13 0 20 223.4 10.0 13 0 22 125.9 12.0 13 0 23 24.1 17.1 13 0 24 128.0 10.9 13 0 25 205.5 14.7 13 0 26 130.6 17.5 13 1 0 266.9 4.4 13 1 1 205.2 3.8 13 1 2 256.4 5.3 13 1 3 380.7 5.7 13 1 4 22.6 11.2 13 1 5 103.2 5.1 13 1 6 340.9 5.6 13 1 7 20.6 10.4 13 1 8 327.4 5.1 13 1 9 48.8 11.7 13 1 10 108.5 6.4 13 1 11 64.7 12.8 1 12 161.2 6.9 1 13 54.6 13.5 1 14 196.4 3.9 1 I5 102.5 8.2 1 16 26.0 12.3 1 17 106.6 6.5 1 18 170.9 5.4 1 19 112.8 8.0 1 20 143.4 20.6 1 21 26.1 12.9 1 22 76.6 14.2 1 23 128.7 9.1 1 24 143.7 6.9 1 25 74.8 12.4 1 26 20.6 10.4 2 0 323.0 5.1 2 1 496.1 6.8 2 2 175.6 5.6 2 3 241.0 4.2 2 4 93.7 7.8 2 5 97.3 5.3 2 6 210.2 5.2 2 7 30.4 13.2 2 8 168.6 5.8 2 9 184.1 4.0 2 10 127.1 6.3 2 11 173.2 4.3 2 12 208.6 5.9 2 13 181.5 4.1 2 14 36.1 12.0 2 15 199.6 4.9 2 16 108.3 6.1 2 17 101.8 7.1 2 18 40.8 16.0 2 19 47.9 15.3 2 20 221.5 10.4 2 21 40.9 15.4 2 22 86.7 10.0 2 23 136.7 9.4 2 24 89.2 10.4 2 25 34.9 15.7 2 26 61.5 15.1 3 0 481.9 6.9 3 1 114.6 4.6 3 2 306.7 4.8 3 3 72.5 6.2 3 4 106.3 6.7 3 5 258.4 4.8 3 6 227.9 4.5 3 7 39.9 13.6 3 8 89.7 7.8 3 10 76.3 11.4 3 11 204.4 4.2 3 12 94.9 6.9 3 13 45.1 14.5 3 14 164.9 5.2 3 15 27.1 12.2 3 16 86.6 6.7 3 17 82.0 8.0 3 18 75.9 8.8 3 19 23.1 11.2 3 20 202.2 15.3 3 22 107.9 7.9 3 23 166.5 6.6 3 24 86.0 11.0 3 25 47.4 15.7 3 26 53.4 15.5 4 0 188.4 4.8 4 1 107.3 5.3 4 2 156.2 4.2 4 3 216.4 6.6 4 4 317.0 4.8 4 5 389.5 6.2 4 6 168.8 4.4 4 7 374.7 5.5 4 8 220.8 4.3 4 9 217.9 5.1 4 10 228.2 4.7 4 11 127.6 4.5 4 12 127.9 5.5 4 13 171.6 4.4 4 14 138.8 4.6 4 15 74.6 8.2 4 16 175.2 4.4 4 17 72.6 8.1 4 18 159.0 4.8 4 19 21.1 10.6 4 20 373.2 14.4 4 21 137.0 6.2 4 22 48.3 16.5 4 23 190.4 5.9 4 24 38.4 16.8 4 25 69.6 15.5 4 26 72.3 13.8 5 0 164.3 5.9 5 1 183.3 5.9 5 2 57.4 7.5 5 3 183.3 6.1 5 4 153.0 6.2 5 5 292.1 4.7 5 6 202.2 4.0 5 7 219.4 4.3 5 8 33.7 13.5 5 9 179.5 4.7 5 10 70.0 7.6 5 11 83.7 7.1 5 12 86.8 8.7 5 13 79.8 7.2 5 14 100.5 5.5 5 15 33.1 12.9 5 16 236.0 4.3 5 17 73.1 9.4 5 18 59.5 11.6 5 19 106.2 6.3 5 20 387.5 11.8 .5 21 72.3 9.8 5 22 49.9 16.8 5 23 50.1 17.0 5 24 104.0 9.7 5 25 65.7 18.1 6 0' 208.2 4.1 6 1 273.1 6.5 6 2 128.2 4.7 6 3 219.2 6.3 6 4 56.4 11.5 6 5 19.7 9.4 6 6 119.1 4.8 6 7 193.2 4.3 6 9 20.5 9.9 6 10 61.0 9.1 6 11 93.7 7.4 6 12 133.3 6.0 6 13 229.5 4.4 6 14 108.1 5.6 6 15 19.2 9.4 6 16 60.3 11.3 6 17 101.3 7.4 6 18 57.8 12.2 6 20 168.2 15.6 6 21 35.1 14.3 6 22 113.3 7.6 6 23 42.3 16.1 6 24 141.3 7.7 6 25 55.8 18.9 PCT/GB98/02542 3 7 0 175.9 3.9 3 7 1 98.8 4.4 3 7 2 138.6 4.7 3 7 3 261.7 3 7 4 242.6 5.3 3 7 5 230.7 4.4 3 7 6 196.3 4.3 3 7 7 26.3 12.8 3 7 8 19.3 9.4 3 7 9 152.2 3 7 10 96.0 5.9 3 7 11 115.7 3 7 12 254.2 4.4 3 7 13 182.7 4.3 3 7 14 230.8 4.8 3 7 15 211.3 5.1 3 7 16 111.5 5.7 3 7 17 134.8 5.6 3 7 18 81.3 11.8 3 7 21 55.8 15.2 3 7 22 67.2 12.8 3 7 23 159.3 8.7 3 7 24 83.5 10.8 3 7 25 46.7 17.0 3 8 0 317.3 8.8 3 8 1 254.5 4.9 3 8 2 173.1 4.1 3 8 3 94.3 4.9 3 8 4 174.9 4.9 3 8 5 345.4 5.6 3 8 6 247.6 5.2 3 8 7 63.6 7.9 3 8 8 99.0 6.6 3 8 9 245.3 4.2 3 8 10 247.8 4.1 3 8 11 161.9 4.6 .3 8 12 71.9 8.1 .3 8 13 90.9 8.9 .3 8 14 92.4 5.8 .3 8 15 224.8 5.6 .3 8 16 132.7 6.9 13 8 17 23.1 10.7 [3 8 18 92.7 8.9 3 8 19 131.7 12.7 13 8 20 84.0 12.0 13 8 21 50.5 16.7 13 8 22 130.4 6.4 13 8 23 78.3 18.8 13 8 24 79.9 16.7 13 8 25 85.4 17.2 13 9 0 221.3 4.8 13 9 1 319.3 5.6 13 9 2 106.2 4.4 13 9 3 207.5 3.9 13 9 4 55.5 10.0 13 9 5 142.3 5.1 13 9 6 281.7 5.1 13 9 7 30.1 12.2 13 9 8 137.2 4.9 13 9 9 99.3 5.8 13 9 10 55.6 14.0 13 9 11 72.4 8.4 13 9 12 117.9 5.2 13 9 13 218.3 4.3 13 9 14 62.8 12.2 13 9 15 145.1 4.6 13 9 16 130.5 5.7 13 9 17 78.0 7.7 13 9 18 41.6 12.7 13 9 19 379.2 10.5 13 9 20 40.2 16.0 13 9 21 33.1 15.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -150- 112.5 8.1 140.9 9.4 26.5 12.4 26.2 12.8 170.9 3.5 206.2 3.8 316.5 5.2 173.9 4.5 75.4 8.0 356.4 5.1 19.0 9.31 15.2 7.6 134.8 5.1 132.1 5.4 157.0 5.2 70.0 6.5 84.5 7.3 79.5 7.9 93.8 8.7 24.5 11.5 76.2 9.8 180.8 4.7 86.9 8.9 272.1 16.4 127.2 9.4 159.0 6.9 139.9 8.1 137.1 7.0 35.1 16.1 27.6 13.4 16.8 7.9 34.1 10.6 329.8 6.7 69.4 8.1 55.9 10.4 56.2 10.9 36.8 13.3 41.9 13.7 137.0 4.8 86.2 6.0 1173.2 4.8 18.6 9.0 245.7 5.0 94.4 6.9 1128.1 5.2 i35.9 14.2 174.0 6.1 117.3 8.2 1158.7 11.4 19.6 9.9 128.2 6.6 196.9 9.3 153.3 7.1 1116.2 8.4 1102.5 9.0 191.3 4.3 139.9 4.2 80.3 5.1 35.4 10.1 217.6 4.6 198.9 4.7 208.0 4.1 171.5 4.1 165.5 5.0 103.9 6.4 0 99.1 5.1 1 109.3 5.8 2 199.3 4.8 3 121.1 5.6 4 202.6 4.3 28.9 12.7 6 99.4 6.9 7 70.7 11.3 8 444.3 12.1 9 93.5 6.8 .0 72.4 11.0 .1 106.1 7.3 .2 117.4 9.3 .3 79.7 10.9 4 85.4 9.9 225.0 5.8 1 159.5 4.8 2 147.5 4.0 3 231.6 4.6 4 312.2 4.8 5 162.1 4.2 6 109.5 4.4 7 169.0 3.9 8 54.4 10.6 9 27.0 11.7 0 109.6 6.1 1 183.8 4.3 2 247.6 4.1 3 50.6 10.9 4 89.5 6.8 5 54.2 11.8 16 33.4 13.1 .7 26.0 12.1 8 64.2 22.0 9 96.4 8.2 !0 33.6 14.5 H 220.5 5.5 !2 157.1 5.8 D3 37.4 16.4 M4 39.9 16.4 0 110.7 3.7 1 164.1 4.3 2 46.6 10.9 3 79.1 4.6 4 144.8 4.5 5 30.4 11.3 7 132.5 3.9 8 147.0 4.0 9 93.2 5.4 10 79.1 7.6 11 78.1 7.4 12 104.8 5.4 13 152.7 4.3 14 117.9 5.2 15 84.0 7.1 16 66.5 10.9 17 292.6 10.7 19 65.3 10.5 20 120.5 7.2 21 193.1 7.1 22 35.5 14.8 23 137.8 8.3 0 140.2 3.8 1 85.8 7.2 2 181.1 4.6 3 69.6 6.0 4 113.6 5.0 5 18.4 9.0 6 165.1 3.9 7 197.2 5.3 8 108.3 4.9 9 38.4 12.2 10 88.7 6.1 11 93.6 5.3 12 127.9 6.6 13 99.6 5.3 14 194.2 4.6 15 19.5 9.6 17 376.3 39.7 15 181 15 191 15 201 15 21 15 22 15 23 16 0 1 16 1 16 2 1 16 3 16 4 16 5 2 16 6 2 16 7 16 8 16 9 1 16 10 16 11 16 12 16 14 16 15 16 16 16 17 16 18 16 19 16 20 16 21 16 22 16 23 17 0 17 1 17 2 3 17 3 1 17 4 2 17 5 17 6 2 17 7 2 17 8 1 17 9 1 17 10 17 11 17 12 17 13 17 14 17 15 17 16 17 17 17 18 17 19 17 20 17 21 17 22 18 0 18 1 18 2 18 3 18 4 18 5 18 6 18 7 18 8 18 9 18 10 18 11 18 12 18 13 18 14 18 15 18 16 18 17 118 18 118 19 142.2 196.6 52.9 35.8 47.9 22.6 64.8 ~5.9 05.9 ~9.4 ~0.2 10.9 12.8 14.3 )2.7 25.4 108.3 153.1 111.6 111.0 107.3 380.9 113.5 124.1 65.8 148.0 45.5 93.0 93.3 15.7 86.2 .27.7 97.9 09.2 17.0 ~43.1 23.8 .27.2 69.0 129.4 173.3 70.8 137.3 87.3 32.7 200.7 189.5 175.2 120.0 153.9 146.7 31.4 320.8 191.3 144.5 202.5 39.1 132.9 100.5 151.3 130.4 260.2 92.0 160.' 87.2 88.8 47.5 395.

3 8.6 131 96.2 144.

8.1 5.1 6.2 15.9 15.7 11.1 4.1 6.5 4.2 8.3 9.1 4.0 4.5 10.4 7.1 4.4 5.0 4.9 6.0 6.3 6.8 10.4 6.5 6.1 12.3 8.9 15.2 12.0 11.4 7.6 9.0 5.6 3.7 4.0 8.3 4.2 4.1 4.4 3.9 5.0 4.9 8.6 6.5 6.0 14.8 7.0 5.2 4.7 5.8 6.5 5.9 13.9 4.4 3.9 3.4 7.6 8.6 5.9 5.4 4.1 4.4 4.3 6.0 7 3.9 6.4 7.6 14.2 1 14.0 13.3 2 6.1 12.0 4 6.9 39.1 15.2 119.0 7.8 184.9 6.8 229.2 3.8 103.5 4.8 205.2 3.6 150.4 114.7 112.0 3.9 71.2 6.2 123.8 4.9 96.3 26.6 11.1 104.7 5.3 123.5 4.8 78.7 8.7 23.0 10.7 410.5 15.3 26.8 12.2 29.1 12.8 114.7 6.7 29.0 13.2 80.4 12.8 39.5 14.6 130.7 7.*2 168.4 3.4 164.1 4.2 256.6 4.3 13.1 228.1 3.8 105.7 167.4 4.4 60.0 114.8 5.1 156.4 4.9 121.3 6. 3 149.4 5.2 37.8 14.7 235.2 15.2 126.8 5.8 79.4 9.1 217.9 4.3 108.7 116.5 7.9 110.7 6.7 110.6 9.9 185.7 3.6 203.2 17.5 8.7 87.3 4.3 69.2 5.3 102.8 89.3 5.1 271.5 4.4 223.4 4.8 105.9 4.7 1 207.5 4.4 74.0 125.8 11.9 1137.4 6.3 i16.3 8.2 i67.3 10.8 1 94.1 1 115.9 8.6 33.0 15.0 23.7 11.2 219.6 5.1 106.0 3.8 101.4 75.2 212.4 4.3 179.1 4.9 SUBSTITUTE SHEET (RULE 26) WO 99/1 0379 1- 13 22 6 152.6 4.1 13 22 7 88.4 5.3 13 22 8 142.3 4.4 13 22 9 80.8 6.8 13 22 10 24.0 11.1 13 22 12 22.0 10.9 13 22 13 26.4 12.5 13 22 14 148.7 5.4 13 22 15 117.7 10.2 13 22 16 153.2 5.0 13 22 17 27.9 13.8 13 22 18 89.3 7.3 13 22 19 193.8 5.7 13' 23 0 166.3 3.2 13 23 1 196.7 3.5 13 23 2 131.3 6.2 13 23 3 155.9 5.7 13 23 4 147.8 3.3 13 23 5 88.6 4.2 13 23 6 186.7 4.1 13 23 7 109.6 5.5 13 23 8 168.4 4.1 13 23 9 259.2 4.9 13 23 12 80.7 6.1 13 23 13 121.3 4.8 13 23 14 61.9 13.1 13 23 15 54.9 13.7 13 23 16 26.2 12.6 13 23 17 102.3 7.0 13 23 18 87.4 11.8 13 23 19 63.2 18.7 13 24 0 21.9 9.8 13 24 1 104.2 4.9 13 24 2 101.1 5.6 13 24 3 132.7 3.6 13 24 4 114.0 6.9 13 24 5 74.8 6.4 13 24 6 65.2 6.5 13 24 7 124.4 4.4 13 24 9 131.0 25.5 13 24 10 81.1 7.9 13 24 11 60.0 12.4 13 24 12 90.8 7.8 13 24 13 78.4 10.1 13 24 14 107.4 7.5 13 24 15 143.3 5.1 13 24 16 119.4 6.2 13 24 17 79.5 9.6 13 24 18 52.9 14.1 13 25 0 83.4 9.2 13 25 1 183.5 3.2 13 25 2 119.3 3.8 13 25 3 184.5 5.2 13 25 4 94.7 4.1 13 25 5 60.2 12.5 13 25 6 223.7 9.8 13 25 8 46.8 13.7 13 25 9 193.6 4.9 13 25 10 34.9 13.2 13 25 11 99.4 6.1 13 25 12 158.1 4.7 13 25 13 185.7 4.5 13 25 14 67.5 9.4 13 25 15 60.7 12.7 13 25 16 102.2 7.4 13 25 17 30.1 12.6 13 26 0 134.0 3.6 13 26 1 24.8 10.3 13 26 2 223.8 5.6 13 26 3 73.9 21.2 13 26 4 312.8 13.2 13 26 5 154.8 9.5 13 26 7 90.2 6.7 13 26 8 158.5 4.2 13 26 9 96.3 6.3 13 26 10 73.8 9.4 13 26 11 96.0 6.4 13 26 12 95.4 7.7 13 26 13 37.3 13.3 13 26 14 129.3 8.7 13 26 15 117.7 6.0 13 26 16 69.1 11.3 13 27 0 256.1 19.6 13 27 1 153.0 14.9 13 27 2 83.4 27.3 13 27 3 188.4 4.6 13 27 4 70.0 6.6 13 27 5 38.6 14.9 13 27 6 17.3 8.0 13 27 7 139.6 5.3 13 27 8 92.2 6.2 13 27 9 218.1 5.5 13 27 10 74.1 7.7 13 27 11 106.9 8.9 13 27 12 160.5 5.1 13 27 13 42.9 14.3 13 27 14 164.8 4.6 1 3 27 15 23.9 11.1 13 28 0 165.9 5.8 13 28 1 113.7 4.7 13 28 2 68.3 5.9 13 28 3 224.3 5.2 13 28 4 89.2 4.2 13 28 5 111.9 5.4 13 28 6 47.0 10.4 13 28 7 103.9 5.6 13 28 8 79.9 6.2 13 28 9 60.4 12.4 13 28 10 154.0 6.7 13 28 11 45.0 13.0 13 28 12 89.9 6.9 13 28 13 56.2 11.1 13 28 14 26.9 11.9 13 29 0 120.6 3.6 13 29 1 254.3 6.5 13 29 2 56.7 11.0 13 29 3 114.7 5.2 13 29 4 83.8 9.5 13 29 5 146.1 3.8 13 29 6 237.9 5.3 13 29 7 140.9 4.1 13 29 8 232.0 4.4 13 29 9 73.1 8.7 13 29 10 19.1 9.5 13 29 11 80.1 7.6 13 29 12 77.2 8.8 13 29 13 32.4 14.1 13 30 0 144.7 6.2 13 30 1 93.7 3.9 13 30 2 110.1 5.1 13 30 3 71.5 6.5 13 30 4 109.3 3.9 13 30 5 62.2 13.3 13 30 6 193.4 4.8 13 30 7 166.3 5.4 13 30 8 66.9 9.0 13 30 9 28.2 11.0 13 30 11 159.1 5.6 13 30 12 41.7 14.3 13 31 0 160.1 4.4 13 31 1 91.7 8.9 13 31 2 510.8 34.7 13 31 3 95.6 4.3 13 31 4 81.3 5.0 13 31 5 53.2 17.1 13 31 6 154.3 3.6 13 31 7 104.3 4.1 13 31 8 20.9 9.3 13 31 9 83.8 6.9 13 31 10 92.7 6.8 13 32 0 137.7 3.8 13 32 1 64.2 12.8 13 32 2 63.1 7.1 13 32 3 29.6 13.0 13 32 4 60.1 6.7 13 32 5 123.1 11.0 13 32 6 102.4 7.7 13 32 7 172.4 5.4 13 32 8 42.7 13.5 13 33 0 81.6 5.3 13 33 1 123.7 7.1 13 33 2 45.0 10.6 13 33 3 162.3 8.4 13 33 4 33.2 11.5 13 33 5 104.6 5.1 13 33 6 128.7 6.2 13 34 0 79.7 5.2 13 34 1 51.5 12.5 13 34 2 26.5 12.0 14 0 0 44.4 24.9 14 0 1 235.7 6.2 14 0 2 19.8 13.1 14 0 3 161.5 11.6 14 0 4 54.3 17.5 14 0 5 17.5 12.6 14 0 6 101.3 14.5 14 0 7 176.0 6.4 14 0 8 27.4 17.1 14 0 9 177.4 5.8 14 0 10 197.3 6.4 14 0 11 101.0 10.7 14 0 12 146.7 9.5 14 0 13 184.1 6.8 14 0 14 167.9 8.3 14 0 15 20.9 15.1 14 0 16 60.5 22.1 14 0 17 177.1 12.0 14 0 19 16.2 12.1 14 0 20 46.4 22.3 14 0 21 94.2 15.5 14 0 22 183.2 10.0 14 0 23 135.0 9.5 14 0 24 52.7 25.5 14 1 0 159.0 4.2 14 1 1 77.3 5.2 14 1 2 244.8 5.1 14 1 3 155.2 7.4 14 1 4 141.8 4.8 14 1 6 181.8 4.6 14 1 7 93.4 7.4 14 1 8 182.2 4.2 14 1 9 262.3 4.6 14 1 10 205.3 4.6 14 1 11 91.1 9.6 14 1 12 85.6 9.9 14 1 13 180.9 4.3 14 1 14 112.5 6.3 14 1 15 97.5 7.0 14 1 16 151.5 5.9 14 1 17 215.2 5.9 14 1 18 100.5 9.2 14 1 19 20.6 10.4 14 1 20 96.1 9.9 14 1 21 94.3 11.3 14 1 22 123.3 9.0 14 1 23 28.5 13.4 PCT/GB98/02542 4 1 24 47.7 16.8 4 2 0 270.1 4.4 4 2 1 240.4 4.2 4 2 2 26.9 11.1 4 2 3 175.8 6.8 4 2 4 145.0 4.4 4 2 5 49.7 13.8 4 2 6 100.0 4 2 7 144.2 4.8 4 2 8 104.9 6.8 4 2 9 80.3 6.4 4 2 10 121.6 5.8 4 2 11 26.4 12.1 4 2 12 128.4 4 2 13 68.1 8.6 4 2 14 113.8 4 2 15 114.4 4 2 16 124.4 4 2 17 28.5 12.9 4 2 18 20.2 10.2 4 2 19 27.2 13.7 4 2 20 92.3 13.0 4 2 21 96.0 9.8 4 2 22 27.4 13.7 4 2 23 20.1 10.0 4 2 24 69.7 14.1 4 3 0 162.1 3.8 4 3 1 273.1 5.1 4 3 2 85.2 5.9 4 3 3 218.9 6.2 4 3 4 249.3 4.4 4 3 5 253.9 4.7 4 3 6 25.6 11.9 4 3 7 119.2 4 3 8 185.0 5.7 4 3 9 41.5 13.9 4 3 10 91.2 7.7 4 3 11 200.2 4 3 12 210.6 4.2 4 3 13 143.7 5.6 4 3 14 131.0 5.8 4 3 15 58.2 12.0 4 3 16 169.6 4.8 4 3 17 36.8 14.5 4 3 18 55.8 21.0 4 3 20 25.2 12.1 4 3 21 33.2 14.3 .4 3 22 158.6 9.7 .4 3 23 101.8 9.4 4 3 24 107.2 14 4 0 220.1 3.9 4 4 1 340.3 8.3 14 4 2 129.9 5.7 14 4 3 56.2 6.9 14 4 4 82.6 7.9 14 4 5 211.3 4.3 14 4 6 98.5 7.2 14 4 7 394.3 5.9 14 4 8 114.0 5.7 14 4 9 115.9 5.6 14 4 10 195.6 4.6 14 4 11 124.4 5.3 14 4 12 135.1 5.8 14 4 13 32.7 13.9 14 4 14 87.1 14 4 15 108.7 14 4 16 73.2 9.7 14 4 17 174.1 6.1 14 4 18 141.7 13.0 14 4 19 57.2 16.6 14 4 20 182.6 5.2 14 4 21 109.8 9.6 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -152- 4 22 80.4 11.2 4 23 111.2 .10.0 4 24 87.5 12.0 0 111.7 4.1 1 297.2 5.4 2 52.7 11.0 3 221.4 4.7 4 217.4 6.0 5 243.3 4.5 6 154.8 4.6 7 137.7 6.1 8 158.9 4.3 9 186.3 4.3 10 161.0 4.6 11 125.0 5.3 12 159.8 5.5 13 95.7 7.3 14 38.6 13.4 15 69.0 9.5 16 28.7 13.5 17 119.5 7.5 18 319.0 14.4 19 135.5 6.6 20 61.3 12.4 21 94.5 10.8 22 186.0 6.2 23 63.3 .18.6 24 61.0 16.9 6 0 142.1 6.7 6 1 157.5 3.8 6 2 154.7 3.8 6 4 108.6 6.6 6 5 156.4 5.1 6 6 134.0 5.3 6 7 59.6 11.9 6 8 50.4 11.5 6 9 115.6 4.9 6 10 51.2 11.1 6 11 202.3 4.5 6 12 38.8 13.5 6 13 243.4 4.9 6 14 97.7 8.9 6 15 48.2 14.4 6 16 180.5 4.5 6 17 24.9 11.7 6 18 294.8 9.7 6 19 152.1 6.8 6 20 18.7 9.4 6 21 89.6 9.9 6 22 98.4 9.9 6 23 54.7 18.9 -6 24 24.8 12.1 7 0 128.8 4.1 7 1 136.5 5.2 7 2 169.5 3.5 7 3 148.3 3.7 7 4 248.7 5.2 7 5 119.9 5.7 7 6 277.1 4.9 7 7 188.5 4.5 7 8 214.4 4.3 7 9 63.7 8.1 7 10 73.8 7.8 7 11 126.7 5.4 7 12 104.4 7.5 7 13 94.1 6.4 7 14 57.0 12.2 7 15 124.1 6.4 7 16 126.7 6.4 7 17 22.5 11.2 7 18 157.5 13.4 7 19 121.9 6.8 14 7 20 34.5 14.5 14 7 21 153.7 9.7 14 7 22 107.1 9.6 14 7 23 53.2 17.4 14 8 0 107.0 5.6 14 8 1 53.0 10.0 14 8 2 73.0 5.8 14 8 3 24.4 10.5 14 8 4 151.9 8.8 14 8 5 47.6 11.9 14 8 6 115.1 5.6 14 8 7 148.5 5.5 14 8 8 139.3 4.6 14 8 9 99.2 6.5 14 8 10 111.2 7.0 14 8 11 121.9 6.1 14 8 12 207.9 4.4 14 8 13 216.4 4.3 14 8 14 148.7 6.2 14 8 15- 26.2 11L.8- 14 8 16 141.1 5.8 14 8 19 29.8 12.9 14 8 20 129.0 6.9 14 8 21 87.3 10.2 14 8 22 49.1 19.0 14 8 23 58.4 14.4 14 8 24 100.6 9.5 14 9 0 187.9 3.9 14 9 1 160.1 4.2 14 9 2 85.9 6.6 14 9 3 122.4 4.0 14 9 4 224.0 4.6 14 9 5 121.3 4.3 14 9 6 249.6 4.5 14 9 7 87.3 6.5 14 9 8 23.6 10.7 14 9 9 95.4 8.0 14 9 10 38.3 13.9 14 9 11 127.3 4.8 14 9 12 77.6 8.1 14 9 13 133.1 4.7 14 9 14 47.3 11.7 14 9 15 82.8 8.6 14 9 16 169.1 4.3 14 9 17 290.6 14.9 14 9 18 54.4 17.7 14 9 19 148.4 6.9 14 9 20 119.6 7.0 14 9 21 147.2 5.9 14 9 22 80.6 13.0 14 9 23 109.0 8.3 14 10 0 249.6 4.7 14 10 1 184.4 3.6 14 10 2 64.8 8.2 14 10 3 172.4 3.9 14 10 4 183.8 6.3 14 10 5 125.5 4.3 14 10 6 167.0 4.4 14 10 7 22.0 10.4 14 10 8 205.2 4.0 14 10 9 91.8 7.0 14 10 10 70.5 7.3 14 10 11 176.7 4.3 14 10 12 143.5 4.5 14 10 13 206.1 4.5 14 10 14 18.4 8.9 14 10 15 148.1 7.2 14 10 17 436.6 13.1 14 10 18 161.6 6.7 14 10 19 145.8 5.7 14 10 20 23.4 11.3 14 10 21 134.6 8.5 14 10 22 179.7 8.0 14 10 23 132.0 11.7 14 11 0 177.2 6.2 14 11 1 302.5 4.8 14 11 2 171.1 5.3 14 11 3 304.1 4.9 14 11 4 183.8 7.7 14 11 5 177.0 4.6 14 11 6 185.1 4.2 14 11 7 52.6 10.3 14 11 8 154.6 4.9 14 11 9 49.1 11.3 14 11 10 48.6 10.3 14 11 11 151.8 4.5 14 11 12 73.0 9.2 14 11 13 145.9 5.5 14 11 14 48.2 12.2 14 11 15 29.5 12.9 14 11 17 83.5 14.9 14 11 18- 172.5 7.1 14 11 19 80.7 11.7 14 11 20 102.9 10.8 14 11 21 145.7 6.7 14 11 22 27.5 13.1 14 12 0 143.8 3.4 14 12 1 29.0 11.4 14 12 2 81.8 4.8 14 12 3 244.8 5.6 14 12 4 111.1 4.7 14 12 5 142.4 4.3 14 12 6 79.9 6.5 14 12 7 83.5 6.5 14 12 8 67.8 9.4 14 12 9 21.1 10.4 14 12 10 173.2 4.2 14 12 11 72.1 9.8 14 12 12 52.7 13.3 14 12 13 202.3 4.2 14 12 14 153.4 6.0 14 12 15 37.3 15.0 14 12 16 406.6 15.8 14 12 17 35.3 14.0 14 12 18 136.9 6.0 14 12 19 187.1 7.5 14 12 20 196.4 7.4 14 12 21 113.8 8.9 14 12 22 129.0 8.3 14 12 23 79.9 27.4 14 13 0 209.5 3.7 14 13 1 178.0 4.4 14 13 2 140.2 4.4 14 13 3 156.0 6.2 14 13 4 186.9 3.4 14 13 5 46.2 11.2 14 13 6 33.4 12.4 14 13 7 146.2 4.7 14 13 8 41.7 12.3 14 13 9 24.9 11.3 14 13 10 86.1 8.2 14 13 11 113.7 5.8 14 13 12 169.6 4.4 14 13 13 118.7 6.2 14 13 14 85.5 9.3 14 13 16 162.2 11.0 14 13 17 19.7 10.0 14 13 18 122.1 7.8 14 13 19 27.7 13.1 14 13 20 121.7 8.0 14 13 21 147.0 7.5 14 13 22 32.4 14.7 14 14 0 309.9 5.4 14 14 1 59.8 6.8 14 14 2 149.8 4.3 14 14 3 51.1 6.8 14 14 4 44.2 14.3 14 14 5 137.2 4.8 14 14 6 123.6 4.3 14 14 7 68.9 7.3 14 14 8 105.1 5.7 14 14 9 125.6 14 14 10 95.2 5.7 14 14 11 63.1 13.4 14 14 12 131.2 5.4 14 14 13 26.8 12.7 14 14 14 48.8 14.2 14 14 15 388.0 12.5 14 14 17 164.0 5.4 14 14 18 114.9 14 14 19 96.0 8.9 14 14 20 30.5 13.9 14 14 21 28.5 13.2 14 14 22 139.2 8.3 14 15 0 26.7 10.6 14 15 1 68.9 14 15 2 134.7 4.8 14 15 3 65.6 7.1 14 15 4 53.3 10.0 14 15 5 98.6 7.6 14 15 6 181.9 4.8 14 15 7 99.9 5.2 14 15 8 40.7 11.3 14 15 9 82.5 6.7 14 15 10 104.4 5.9 14 15 11 143.5 4.3 14 15 12 127.6 6.2 14 15 13 18.0 14 15 14 106.0 12.9 14 15 16 121.8 6.9 14 15 17 84.7 9.9 14 15 18 70.5 13.4 14 15 19 122.0 7.7 14 15 20 76.7 11.7 14 15 21 48.8 15.6 14 16 0 176.1 3.4 14 16 1 79.6 6.4 14 16 2 95.8 14 16 3 167.8 4.1 14 16 4 107.6 4.4 14 16 5 62.8 6.4 14 16 6 170.5 4.8 14 16 7 132.8 4.4 14 16 8 112.6 14 16 9 205.0 4.3 14 16 10 170.9 14 16 11 145.3 6.4 14 16 12 121.9 14 16 13 15.7 7.9 14 16 14 231.9 14.5 14 16 15 25.7 12.0 14 16 16 193.5 4.8 14 16 17 160.4 5.7 14 16 18 91.9 10.2 14 16 19 55.6 16.5 14 16 20 103.5 12.2 14 16 21 123.1 11.1 14 17 0 21.5 9.8 14 17 1 201.5 14 17 2 126.5 4.9 14 17 3 160.6 3.7 14 17 4 137.9 14 17 5 30.8 10.7 14 17 6 139.0 4.1 14 17 7 140.2 14 17 8 86.0 6.3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -153- 14 17 9 71.0 7.3 14 17 10 117.1 6.2 14 17 11 105.2 6.5 14 17 12 92.7 7.7 14 17 13 299.5 13.6 14 17 15 160.5 5.2 14 17 16 47.4 14.2 14 17 17 77.1 9.5 14 17 18 207.2 5.5 14 17 19 60.8 16.3 14 17 20 107.3 9.8 14 17 21 52.7 16.7 14 18 0 130.2 3.6 14 18 1 166.9 4.0 14 18 2 127.6 4.4.

14 18 3 21.2 9.5 14 18 4 142.6 4.0 14 18 5 182.4 4.1 14 18 6 68.3 9.6 14 18 7 32.3 12.0 14 18 8 65.0 8.5 14 18 9 171.3 5.1 14 18 10 168.1 9.6 14 18 11 20.6 9.9 14 18 12 165.8 18.5 14 18 13 20.0 10.1 14 18 14 68.9 9.4 14 18 15 38.7 14.1 14 18 16 131.1 9.1 14 18 17 100.1 7.9 14 18 18 154.3 6.2 14 18 19 120.5 8.5 14 18 20 31.1 14.2 14 19 0 199.7 4.4 14 19 1 154.3 6.6 14 19 2 128.2 3.7 14 19 3 76.5 6.3 14 19 4 22.4 9.7 14 19 5 76.1 6.7 14 19 6 136.7 4.3 14 19 7 69.8 9.6 14 19 8 219.7 4.5 14 19 9 88.0 6.9 14 19 10 154.0 4.2 14 19 11 148.4 11.1 14 19 12 146.1 10.8 14 19 13 31.9 14.2 14 19 14 119.8 8.5 14 19 15 123.4 6.0 14 19 16 81.2 11.1 14 19 17 24.1 12.0 14 19 18 123.3 6.9 14 19 19 53.5 13.4 14 19 20 97.7 21.5 14 20 0 70.1 6.8 14 20 1 108.7 4.1 14 20 2 207.0 4.4 14 20 3 132.8 3.7 14 20 4 78.2 6.6 14 20 5 18.5 9.3 14 20 6 107.6 5.3 14 20 7 133.5 4.8 14 20 8 161.8 6.3 14 20 9 30.1 12.7 14 20 10 92.0 33.0 14 20 11 177.6 17.5 14 20 12 33.5 14.9 14 20 13 153.0 7.3 14 20 14 159.0 5.5 14 20 15 116.7 6.9 14 20 16 32.1 14.3 14 20 17 20.9 10.6 14 20 18 62.4 17.7 14 20 19 24.0 11.8 14 21 0 92.1 6.2 14 21 1 51.1 15.0 14 21 2 66.7 8.0 14 21 3 91.8 5.6 14 21 4 132.8 4.7 14 21 5 125.8 4.4 14 21 6 130.3 7.4 14 21 7 80.0 7.0 14 21 8 16.1 8.1 14 21 10 110.5 19.8 14 21 11 89.9 7.1 14 21 12 17.6 8.8 14 21 13 91.6 6.8 14 21 14 131.6 6.6 14 21 15 240.3 5.8 14 21 16 165.3 11.6 14 21 17 161.2 6.2 14 21- 18 98.2 7.8 14 22 0 109.7 5.3 14 22 1 182.0 4.0 14 22 2 245.3 6.1 14 22 3 192.8 4.6 14 22 4 138.7 4.6 14 22 5 216.3 5.7 14 22 8 269.7 14.5 14 22 10 63.8 9.3 14 22 11 18.5 9.3 14 22 12 86.7 11.6 14 22 13 136.5 5.8 14 22 14 67.8 10.4 14 22 15 59.2 15.9 14 22 16 76.6 11.5 14 22 17 49.8 15.5 14 22 18 83.7 11.3 14 23 0 164.1 3.8 14 23 1 19.9 9.5 14 23 2 22.6 11.1 14 23 3 115.6 6.7 14 23 4 103.2 10.3 14 23 5 86.8 5.3 14 23 7 60.6 23.7 14 23 8 155.0 5.5 14 23 9 38.0 13.8 14 23 10 66.3 10.3 14 23 11 204.6 4.7 14 23 12 18.5 9.3 14 23 13 27.4 12.5 14 23 14 27.3 12.5 14 23 15 100.5 6.6 14 23 16 21.7 10.8 14 23 17 118.5 10.9 14 24 1 70.2 14.1 14 24 2 53.2 14.4 14 24 3 145.8 11.1 14 24 4 225.6 12.2 14 24 5 42-.7 15.4 14 24 6 27.4 11.9 14 24 7 153.2 4.1 14 24 8 105.5 6.5 14 24 9 62.8 10.1 14 24 10 94.2 6.6 14 24 11 22.0 10.7 14 24 12 138.0 5.9 14 24 13 138.1 5.5 14 24 14 39.2 14.7 14 24 15 20.5 10.3 14 24 16 20.7 10.2 14 25 0 147.8 21.2 14 25 1 114.0 10.2 14 25 2 62.7 8.7 14 25 3 169.1 3.9 14 25 4 133.6 4.6 14 25 5 19.0 9.0 14 25 6 199.5 4.0 14 25 7 90.1 8.3 14 25 8 82.4 6.2 14 25 9 25.5 11.4 14 25 10 55.9 12.3 14 25 11 179.7 5.2 14 25 12 104.3 7.4 14 25 13 60.5 12.5 14 25 14 170.0 5.5 14 25 15 30.6 13.3 14 26 0 128.5 3.3 14 26 1 149.4 6.6 14 26 2 53.2 9.8 14 26 3 140.0 6.9 14 26 4 96.3 5.5 14 26 5 109.3 6.0 14 26 6 21.5 10.1 14 26 7 282.3 5.4 14 26 8 31.8 13.1 14 26 9 160.4 5.9 14 26 10 156.7 6.5 14 26 11 30.2 13.4 14 26 12 94.0 7.3 14 26 13 77.4 9.7 14 27 0 70 .1 12.5 14 27 1 24.6 10.4 14 27 2 124.7 10.4 14 27 3 201.7 5.1 14 27 4 145.2 3.8 14 27 5 94.6 6.6 14 27 6 49.3 11.2 14 27 7 38.9 13.1 14 27 8 193.0 10.6 14 27 9 17.7 8.7 14 27 10 39.2 14.7 14 27 11 40.9 12.8 14 27 12 19.8 9.8 14 28 0 133.0 5.1 14 28 1 173.8 4.5 14 28 2 107.8 5.3 14 28 3 47.4 8.7 14 28 4 215.6 4.6 14 28 5 68.7 9.0 14 28 6 84.0 5.3 14 28 7 109.2 6.9 14 28 8 118.3 6.4 14 28 9 20.0 9.9 14 28 10 100.6 8.2 14 28 11 62.9 13.5 14 28 12 164.3 6.0 14 29 0 44.5 9.3 14 29 1 60.4 14.5 14 29 2 158.2 4.8 14 29 3 85.4 6.4 14 29 4 131.5 4.8 14 29 5 140.8 4.3 14 29 6 105.8 5.5 14 29 7 168.6 4.8 14 29 8 53.6 7.5 14 29 9 43.3 11.2 14 29 10 143.5 4.8 14 30 0 20.8 9.8 14 30 1 38.2 10.0 14 30 2 64.8 8.2 14 30 3 77.2 9.4 14 30 4 164.8 4.3 14 30 5 78.3 11.4 14 30 6 177.7 4.5 14 30 7 147.3 4.3 PCT/GB98/02542 14 30 8 64.0 12.4 14 30 9 208.0 5.3 14 31 0 18.4 9.2 14 31 1 66.4 12.8 14 31 2 67.4 14 31 3 139.8 4.9 14 31 4 40.4 10.5 14 31 5 101.0 8.3 14 31 6 76.7 7.1 14 31 7 56.3 12.8 14 32 0 87.4 4.8 14 32 1 106.7 12.4 14 32 2 42.8 15.1 14 32 3 18.7 8.8 15 0 0 264.6 15 0 1 114.6 15 0 2 52.2 14.4 15 0 3 116.4 13.2 15 0 4 21.5 13.2 15 0 5 135.3 7.9 15 0 6 150.4 12.9 15 0 7 176.1 6.1 15 0 8 140.4 15 0 9 332.9 7.2 15 0 10 109.8 9.7 15 0 11 202.9 9.8 15 0 12 90.7 12.2 I5 0 13 205.5 7.1 15 0 14 24.6 16.5 15 0 15 161.2 8.4 15 0 16 80.6 25.5 15 0 17 21.4 15.4 15 0 18 28.1 18.0 15 0 19 19.1 14.0 15 0 20 18.3 13.2 15 0 21 27.9 19.8 15 0 22 116.0 1312 15 1 0 104.8 15 1 1 47.0 15 I 2 93.2 5.6 15 1 3 82.1 12.1 15 1 4 114.9 4.1 15 1 5 89.1 7.2 15 1 6 62.2 11.2 15 1 7 192.8 4.1 15 I 8 66.1 8.9 15 1 9 24.0 11.5 15 1 10 27.2 12.4 15 1 11 89.9 9.7 15 1 12 140.6 15 1 13 50.6 14.3 15 1 14 78.6 10.5 15 1 15 137.2 15 1 16 40.6 16.1 15 1 18 141.6 6.3 15 1 19 86.5 13.9 15 1 20 102.0 8.8 15 1 21 55.5 16.9 15 1 22 169.5 15 1 23 83.9 17.5 15 2 0 93.4 9.4 15 2 1 169.8 3.7 15 2 2 130.7 15 2 3 119.5 15 2 4 96.0 5.3 15 2 5 80.1 8.1 15 2 6 139.9 5.2 15 2 7 25.9 11.2 15 2 8 155.9 4.7 15 2 9 48.9 13.1 15 2 10 169.8 5.4 15 2 11 108.4 6.3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -154- 2 12 106.0 6.6 2 13 153.8 6.0 2 14 145.2 9.9 2 15 72.3 11.8 2 16 142.6 9.6 2 17 20.6 10.3 2 18 124.2 9.1 2 19 95.8 11.8 2 20 52.6 15.2 2 21 24.5 12.4 2 22 141.8 11.4 3 0 80.3 11.5 3 1 144.4 4.3 3 2 75.3 8.0 3 3 219.4 4.8 3 4 163.6 3.8 3 5 110.7 6.0 3 6 201.6 4.9 3 7 169.3 4.1 3 8 116.8 5.1 3 9 55.0 10.9 3 10 104.4 6.5 3 11 155.5 5.1 3 12 78.7 8.3 3 13 213.4 5.2 3 14 86.7 8.2 3 15 195.3 5.5 3 16 97.5 20.2 3 18 83.8 13.5 3 19 98.4 12.9 3 20 44.1 16.7 3 21 30.5 15.0 3 22 117.8 8.4 3 23 67.8 15.5 4 0 57.8 15.9 4 1 196.8 3.9 4 2 245.8 4.9 4 3 160.7 6.0 4 4- 53.2 7.7 4 5 131.9 8.3 4 6 67.9 9.1 4- 7 134-.9 5.9 4 8 213.2 4.2 4 9 147.1 5.1 4 10 34.5 15.7 4 11 49.8 12.7 4 12 142.1 4.9 4 13 101.7 8.5 4 14 135.1 5.6 4 15 89.7 9.7 4 16 400.8 53.1 -4 18 26.7 12.8 4 19 53.2 16.7 4.20 141.7 7.4 4 22 64.7 16.7 4 23 23.0 11.6 0 154.9 4.6 1 207.3 4.2 2 86.5 6.3 3 73.4 8.4 4 44.1 10.8 5 177.8 4.3 6 257.4 5.3 7 192.9 4.2 8 169.2 5.2 9 109.6 7.6 10 148.6 5.9 11 103.7 6.5 12 161.1 4.9 13 61.9 14.9 14 50.4 14.4 15 91.7 9.4 5 16 276.4 8.8 5 17 71.6 11.4 5 18 97.0 10.5 5 19 110.0 8.5 5 20 121.6 8.2 5 21 18.8 9.5 5 22 70.6 17.4 5 23 80.8 17.3 6 0 69.5 6.0 6 I 37.1 11.4 6 2 136.3 3.9 6 3 27.9 11.7 6 4 186.3 3.9 6 5 157.9 4.6 6 6 29.6 12.8 6 7 19.6 9.6 6 9 163.7 5.2 6 10 40.7 14.4 6 11 28.6 12.2 6 12 100.9 7.5 6 13 84.6 10-*4 6 14 25.2 12.2 6 15 23.0 11.5 6 16 449.6 15.1 6 17 130.0 6.9 6 18 176.0 5.7 6 19 176.3 9.1 6 20 169.9 6.4 6 21 48.7 17.0 6 22 56.1 14.9 7 0 173.6 3.6 7 1 58.2 11.6 7 2 166.4 4.3 7 3 81.5 6.3 7 4 129.2 3.9 7 5 126.8 6.2 7 6 157.6 7.7 7 7 71.0 10.0 7 8 67.2 9.1 7 9 75.8 7.9 7 10 95.1- 8.9 7 11 167.1 5.1 7 12 119.2 5.7 7 13 178.9 5.7 7 14 77.5 11.1 7 16 76.6 22.7 7 17 112.7 6.7 7 18 39.0 15.3 7 19 55.3 16.6 7 20 131.4 8.2 7 21 42.6 16.3 7 22 123.5 8.4 8 0 44.1 9.9 8 1 191.6 4.4 8 2 139.5 5.4 8 3 100.5 4.9 8 4 61.9 7.6 8 5 136.1 5.8 8 6 150.3 5.8 8 7 19.8 9.6 8 8 135.4 4.5 8 9 56.2 13.1 8 10 102.5 7.8 i8 11 33.5 13.5 i8 12 21.5 10.4 i8 13 151.4 5.5 i8 14 97.8 9.2 i8 15 188.5 14.3 58 16 40.4 15.5 5 8 17 17.3 8.7 5 8 18 81.2 10.2 3 8 19 102.8 10.5 15 8 2 15 8 2 15 9 0 15 9 1 15 92 15 93 15 9 4 15 95 15 9 15 97 15 9 8 15 9 15 9 1 15 9 1 15 9 1 15 9 1 15 9 1 15 9 1 15 9 1 15 9 1 15 9 1 15 9 1 15 9 2 15 9 2 15 9 2 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 10 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 11 15 12 15 12 15 12 15 12 15 12 1 30.0 13.5 2 24.6 11.9 120.2 5.4 133.1 4.7 169.0 3.6 1122.7 3.7 I93.6 5.6 311.4 4.9 188.3 4.3 1144.0 5.1 151.6 13.2 101.3 8.1 0 72.3 9.2 1 240.5 4.5 2 183.4 4.7 3 155.5 5.0 4 30.6 12.6 5 432.6 13.5 6 61.1 15.2 7 93.9 8.0 8 20.1 10.1 9 69.2 16.1 0 22.2 11.0 1 87.6 11.5 2 28.2 13.9 0 126.3 3.8 1 118.9 5.8 2 251.2 4.7 3 41.2 10.8 4 71.3 8.3 5 29.7 12.6 6 176.8 5.1 7 56.2 11.4 8 189.0 5.6 9 156.2 4.9 10 177.7 5.3 11 126.1 7.5 12 157.6 4.8 13 125.3 6.3 14 80.8 12.9 15 128.1 19.6 16 58.0 15.8 17 110.9 8.7 18 100.3 8.2 19 79.3 12.9 20 49.4 18.9 21 32.4 14.5 0 41.7 10.2 1 16.2 8.1 2 74.7 5.8 3 47.6 11.0 4 131.0 6.8 5 94.7 7.2 6 72.3 10.5 7 140.0 5.5 8 97.5 6.2 9 105.3 5.6 10 109.8 6.6 11 38.1 13.3 12 66.6 10.1 13 169.9 4.8 14 259.9 15.4 16 68.9 10.6 18 132.4 7.8 19 143.7 7.7 20 118.5 11.4 21 56.8 16.4 0 87.3 6.9 1 94.8 5.8 2 73.7 5.6 3 119.2 9.3 4 124.1 4.0 PCT/GB98/02542 5 12 5 71.0 8.4 5 12 6 177.7 4.4 5 12 7 124.1 4.6 5 12 8 186.0 4.3 5 12 9 24.6 11.1 5 12 10 64.4 5 12 11 31.2 13.6 5 12 12 140.0 8.2 5 12 13 20.4 10.3 5 12 14 327.6 19.7 5 12 15 64.6 12.0 5 12 16 70.4 12.8 5 12 17 36.4 16.4 5 12 18 152.7 5 12 19 29.6 13.5 5 12 20 45.9 16.8 5 12 21 54.6 16.3 5 13 0 65.0 5 13 1 15.8 7.9 5 13 2 78.0 5.3 5 13 3 111.1 8.6 5 13 4 82.6 5.1 5 13 5 41.7 11.6 5 13 6 92.9 6.1 5 13 7 85.2 6.4 5 13 8 141.1 5.1 5 13 9 138.9 5.8 5 13 10 24.0 11.4 .5 13 11 76.5 15 13 13 285.1 12.8 5 13 14 25.4 12.0 L5 13 15 185.2 5.7 L5 13 16 39.6 13.9 15 13 17 64.3- 13.7 [5 13 18 159.2 7.8 15 13 19 87.6 I5 13 21 177.1 9.8 15 14 0 71.4 15 14 1 84.9 7.4 15 14 2 205.8 3.8 15 14 3 82.9 5.8 15 14 4 30.0 13.2 15 14 5 102.3 6.4 15 14 6 148.2 6.3 15 14 7 83.4 7.7 15 14 8 19.9 10.0 15 14 9 93.7 7. 3 15 14 10 61.6 11.6 15 14 11 48.4 13.6 15 14 13 123.1 34.3 15 14 14 21.1 10.3 15 14 15 40.2 15.4 15 14 16 125.8 6.3 15 14 17 184.0 5.8 15 14 18 63.8 17.3 15 14 19 28.4 13.4 15 15 0 30.3 13.2 15 15 1 19.7 9.4 15 15 2 130.4 4.9 15 15 3 87.4 5.9 15 15 4 127.2 3.9 15 15 5 127.8 15 15 6 35.2 12.8 15 15 7 122.4 6.6 15 15 8 37.0 16.0 15 15 9 177.3 5.4 15 15 10 130.7 6.2 1-5 15 11 20.8 10.1 15 15 12 382.7 15.2 15 15 13 19.6 9.8 15 15 14 131.4 6.3 15 15 15 105.4 7.7 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -155- 15 16 125.5 I5 17 95.1 I5 18 87.6 1 15 19 48.11 15 20 33.3 1 16 0 92.68 16 1 178.3 16 2 188.1 16 3 118.5 16 4 77.2 1 16 5 160.1 16 6 87.2 16 7 253.4 16 8 38.5 1 16 9 104.1 16 11 279.8 16 12 17.1 16 13 80.5 16 14 70.7 16 15 89.8 16 16 81.2 16 17 122.7 16 18 83.0 16 19 100.4 17 0 157.7 17 1 87.8 17 2 115.2 17 3 121.8 17 4 155.5 17 5 126.0 17 6 149.4 17 7 24.7 1 17 8 32.7 1 17 10 348.2 17 11 34.3 17 12 31.1 17 13 51.5 17 14 104.2 17 15 62.6 17 16 86.8 17 17 99.8 17 18 104.1 17. 19 43.4 18 0 133.7 18 1 107.8 18 2 93.6 18 3 61.4 18 4 66.3 18 5 44.2 18 6 54.6 18 7 70.4 18 8 143.5 18 9 404.2 18 10 42.6 18 11 21.7 18 12 62.3 18 13 67.3 18 14 195.1 18 15 155.5 18 16 166.1 18 17 33.1 18 18 85.9 19 0 100.6 19 1 171.4 19 2 65.2 19 3 105.8 19 4 145.2 19 5 70.1 19 6 219.1 19 7 23.0 19 8 341.6 19 9 156.5 6.6 9.0 2.0 8.7 .5.7 .6 3.9 5.8 2.2 4.2 1. 1 4.4 2.6 5.4 10.0 8.7 8.4 11.2 9.4 13.0 8.1 11.0 12.6 3.9 9.4 3.8 4.1 4.4 4.7 6.7 0.9 3.0 12.3 16.2 13.4 17.0 7.0 11.8 9.9 12.9 14.8 17.1 5.4 4.3 8.6 6.9 6.3 11.5 12.0 8.1 5.5 19.0 17.6 10.5 12.5 12.6 5.4 7.2 5.9 14.0 13.5 6.1 4.5 6.0 9.4 6.4 8.5 4.5 11.6 10.7 5.4 15 19 10 91.7 6.8 15 19 11 136.6 5.2 15 19 12 35.0 13.1 15 19 13 145.4 5.7 15 19 14 42.7 14.7 15 19 15 171.2 6.1 15 19 16 144.2 6.6 15 19 17 33.6 13.9 I5 19 18 27.4 13.1 15 20 0 99.6 4.8 15 20 1 128.3 5.1 15 20 2 185.8 6.7 15 20 3 223.2 5.2 I5 20 4 40.5 11.0 15 20 5 160.9 4.1 15 20 6 149.5 19.6 15 20 7 271.1 14.0 15 20 8 19.6 9.9 15 20 10 80.6 7.7 15 20 11 132.3 6.0 15 20 12 63.9 14.0 15 20 13 81.2 9.0 15 20 14 108.4 8.4 15 20 15 23.4 11.5 15 20 16 55.7 16.4 15 20 17 69.5 12.6- 15 21 0 33.7 11.2 15 21 2 14.9 7.4 15 21 3 20.3 10.0 15 21 4 106.7 15.8 15 21 5 268.9 10.8 15 21 6 98.8 6.0 15 21 7 94.3 8.9 15 21 8 72.5 8.1 15 21 9 163.5 5.4 15 21 10 39.1 14.5 15 21 11 68.1 13.1 15 21 12 85.5 8.3 15 21 13 159.4 5.8 15 21 14 147.3 9.2 15 21 15 150.5 6.8 15 21 16 175.5 6.3 15 22 0 136.6 15.2 15 22 1 246.1 10.6 15 22 2 296.6 12.6 15 22 3 325.0 9.9 15 22 5 80.5 10.6 15 22 6 38.8 12.2 15 22 7 124.6 5.4 15 22 8 93.4 9.7 15 22 9 122.0 5.6 15 22 10 30.6 12.7 15 22 11 48.8 13.1 15 22 12 101.6 7.5 15 22 13 89.1 8.2 15 22 14 49.6 13.4 15 22 15 29.0 13.5 15 23 0 15.7 7.9 15 23 2 103.7 5.1 15 23 3 36.0 13.2 15 23 4 130.1 5.1 15 23 5 164.5 4.5 15 23 6 99.8 5.5 15 23 7 76.4 6.3 15 23 8 100.3 8.2 15 23 9 69.5 9.8 15 23 10 102.7 7.6 15 23 11 38.2 14.5 15 23 12 89.0 8.5 15 23 13 129.1 5.1 15 23 14 54.7 13.8 15 23 15 26.1 12.7 15 24 0 80.5 5.0 15 24 1 115.0 5.9 15 24 2 28.0 11.3 15 24 3 23.9 9.9 15 24 4 132.9 5.1 15 24 5 183.5 4.8 15 24 6 83.9 6.1 15 24 7 49.4 13.4 I5 24 8 27.5 12.4 15 24 9 104.0 7.0 15 24 10 25.1 12.1 I5 24 11 121.4 5.6 15 24 12 102.3 8.5 15 24 13 77.0 10.4 15 24 14 36.7 15.4 15 25 0 48.5 13.8 15 25 1 144.3 4.1 15 25 2 74.8 9.3 15 25 4 142.4 4.1 15 25 5 71.0 9.2 15 25 6 90.3 5.0 15 25 7 146.1 7.5 15 25 8 118.3 5.7 15 25 9 47.4 15.2 15 25 10 150.5 5.3 15 25 11 109.6 6.6 15 25 12 89.1 8.1 15 25 13 60.8 12.2 15 26 0 101.3 5.6 15 26 1 107.1 9.0 15 26 2 101.7 5.3 15 26 3 72.8 6.1 15 26 4 41.5 12.3 15 26 5 68.4 7.1 15 26 6 194.1 4.3 15 26 7 44.2 17.2 15 26 8 153.6 8.6 15 26 9 102.9 9.2 15 26 10 55.1 12.5 15 26 11 113.4 7.4 15 27 0 108.1 8.2 15 27 1 130.2 4.2 15 27 2 114.1 6.2 15 27 3 45.7 12.3 15 27 4 156.0 5.6 15 27 5 89.5 10.5 15 27 6 18.9 9.1 15 27 8 36.1 11.1 15 27 9 159.1 5.5 15 27 10 15.8 8.0 15 28 0 44.0 13.2 15 28 1 108.7 4.4 15 28 2 68.7 7.0 I5 28 3 88.3 6.7 15 28 4 138.1 4.3 15 28 5 82.4 5.9 15 28 6 83.6 5.4 15 28 7 79.3 14.7 15 28 8 22.3 11.0 15 28 9 22.9 11.2 15 29 0 137.8 3.8 15 29 1 32.9 14.5 15 29 2 138.2 5.9 15 29 3 85.5 6.2 15 29 4 65.7 9.4 15 29 5 24.7 11.0 15 29 6 24.1 10.9 15 29 7 18.1 9.0 15 30 0 43.5 15.7 15 30 I 91.9 4.8 15 30 2 21.8 10.3 15 30 3 53.0 11.6 15 30 4 99.0 7.1 16 0 0 73.9 7.7 16 0 1 30.2 16.7 16 0 2 36.0 22.8 16 0 3 201.4- 16 0 4 10.3 7.7 16 0 5 93.8 12.9 16 0 6 85.7 20.5 16 0 7 76.5 18.7 16 0 8 96.9 20.7 16 0 9 103.9 8.2 16 0 10 214.7 6.1 16 0 11 70.8 19.5 16 0 12 19.6 13.8 16 0 13 57.6 22.0 16 0 14 532.9 18.9 16 0 15 24.2 17.5 16 0 17 55.8 22.9 16 0 18 78.5 25.4 16 0 19 27.5 19.2 16 0 20 139.9 17.5 16 0 21 34.6 23.8 16 1 0 53.4 7.3 16 1 1 36.4 14.1 16 1 2 144.1 7.9 16 1 3 73.3 16 1 4 106.9 16 1 5 115.2 8.9 16 1 6 19.8 10.1 16 1 7 109.0 7.3 16 1 8 26.0 11.9 16 1 9 129.4 5.1 16 1 10 87.0 8.1 16 1 11 78.6 9.8 16 1 12 132.8 16 1 13 27.0 12.6 16 1 14 533.2 16.2 16 1 16 89.9 16 1 17 152.3 16 1 18 155.1 9.4 16 1 19 79.9 19.8 16 1 20 98.2 11.6 16 1 21 71.2 18.9 16 2 0 140.6 3.6 16 2 1 269.8 5.2 16 2 2 146.6 16 2 3 18.8 9.3 16 2 4 152.5 3.9 16 2 5 148.0 6.3 16 2 6 36.1 15.0 16 2 7 102.2 6.9 16 2 8 140.5 16 2 9 152.7 16 2 10 28.5 12.2 16 2 11 27.4 12.5 16 2 12 53.6 13.1 16 2 13 54.2 15.8 16 2 14 467.4 10.9 16 2 16 94.7 16 2 17 169.9 16 2 19 150.9 10.9 16 2 20 75.5 15.3 16 2 21 78.0 18.4 16 3 0 59.6 7.1 16 3 1 160.5 4.3 16 3 2 53.7 8.6 16 3 3 73.3 16 3 4 119.4 16 3 5 97.5 16 3 6 122.2 8.4 16 3 7 102.8 7.2 16 3 8 91.8 7.2 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -156- 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 3 9 204.8 4.4 3 10 99.8 .6.2 3 11 104.6 8.9 3 12 131.2 5.3 3 13 27.4 13.2 3 14 472.1 13.6 315 27.1 13.1 3 16 115.7 8.5 3 17 36.2 16.3 3 18 92.8 13.9 3 19 58.5 20.2 3 20 146.0 6.9 3 21 34.1 16.0 4 0 78.2 5.3 4 1 30.8 11.8 4 2 25.4 11.0 4 3 36.8 13.3 4 4 212.2 4.8 4 5 124.3 8.1 4 6 87.2 10.0 4 7 94.4 8.2 4 8 31.5 13.0 4 9 90.4 6.6 4 10 27.6 12.3 4 11 61.9 13.0 4 12 149.0 5.0 4 13 28.2 13.9 4 14 286.0 15.6 4 15 128.1 8.8 4 16 115.8 8.6 4 17 98.0 12.9 4 18 25.8 12.6 4 19 73.5 22.7 4 20 78.6 14.2 4 21 66.6 18.5 5 0 223.5 3.9 5 1 119.3 5.1 5 2 117.8 4.9 5 3 167.2 5.1 5 4 66.9 7.3 5 5 35.7 14.8 5 6 39.3 14.9 5 7 179.5 5.4 5 8 20.9 10.3 5 9 101.4 7.1 5 10 95.2 7.7 5 11 123.1 6.4 5 12 35.5 13.7 5 14 115.1 33.1 5 15 100.2 11.1 5 16 94.2 12.0 -5 17 106.4 9.3 5 18 225.7 7.1 5 19 21.9 11.0 5 20 71.9 15.0 5 21 49.9 19.1 6 0 122.0 4.9 6 1 79.3 6.1 6 2 95.2 4.7 6 3 178.6 4.6 6 4 79.2 5.7 6 5 183.7 6.5 6 6 34.3 14.3 6 7 103.8 7.1 6 8 51.5 13.3 6 9 103.5 10.5 6 10 124.0 6.2 6 11 218.5 4.9 6 12 31.4 13.5 6 13 290.3 16.0 6 15 40.9 14.8 6 16 60.8 14.9 16 6 17 147.7 6.9 16 6 18 104.7 10.0 16 6 19 22.0 10.9 16 6 20 30.2 14.4 16 6 21 124.6 8.4 16 7 0 48.1 9.8 16 7 1 183.5 4.6 16 7 2 135.3 8.0 16 7 3 150.1 4.9 16 7 4 15.8 7.8 16 7 5 85.0 7.1 16 7 6 99.8 9.1 16 7 7 105.8 6.4 16 7 8 78.3 8.4 16 7 9 94.9 7.4 16 7 10 148.3 5.1 16 7 11 179.7 5.8 16 7 12 203.6 5.1 16 7 13 492.4 12.0 16 7 14 27.3 13.6 16 7 15 157.0 6.0 16 7 16 87.2 9.1 16 7 17 89.9 11.2 16 7 18 108.2 10.9 16 7 19 225.6 6.2 16 7 20 147.1 8.5 16 8 0 107.6 6.1 16 8 1 43.7 11.7 16 8 2 195.0 4.0 16 8 3 16.0 7.9 16 8 4 126.6 4.0 16 8 5 175.1 5.8 16 8 6 137.0 6.9 16 8 7 138.2 5.2 16 8 8 130.8 5.1 16 8 9 121.6 5.5 16 8 10 173.6 6.0 16 8 11 168.3 5.4 16 8 12- 37.3 15.7 16 8 13 264.4 17.3 16 8 14- 24.1 11.6 16 8 15 111.4 8.7 16 8 16 87.3 9.4 16 8 17 92.9 11.5 16 8 18 56.1 18.7 16 8 19 90.1 11.3 16 8 20 90.7 11.0 16 9 0 77.6 6.9 16 9 1 103.1 6.3 16 9 2 64.0 7.4 16 9 3 154.4 4.2 16 9 4 29.7 12.6 16 9 5 73.2 9.8 16 9 6 189.2 4.8 16 9 7 44.6 14.8 16 9 8 71.9 8.5 16 9 9 103.3 6.5 16 9 10 163.1 5.1 16 9 11 67.8 10.9 16 9 12 313.0 10.3 16 9 14 135.6 5.4 16 9 15 101.1 12.3 16 9 16 138.8 7.5 16 9 17 89.9 9.1 16 9 18 25.2 12.4 16 9 19 45.5 18.0 16 9 20 30.6 14.1 16 10 0 120.5 5.5 16 10 1 122.3 5.6 16 10 2 100.6 6.2 16 10 3 149.9 5.2 16 10 4 87.9 12.5 16 10 5 30.4 13.7 16 10 6 106.7 6.9 16 10 7 164.7 4.3 16 10 8 66.0 8.8 16 10 9 64.1 12.1 16 10 10 48.4 14.4 16 10 12 482.0 20.2 16 10 13 35.0 15.6 16 10 14 19.1 9.5 16 10 15 62.6 13.5 16 10 16 51.2 18.2 16 10 17 120.4 8.1 16 10 18 29.0 13.6 16 10 19 78.5 14.2 16 10 20 45.2 16.4 16 11 0 88.6 8.0 16 11 1 93.7 5.7 16 11 2 102.2 4.7 16 11 3 124.3 8.7 16 11 4 151.7 3.8 16 11 5 84.0 5.7 16 11 6 102.2 6.4 16 11 7 82.6 7.7 16 11 8 71.9 9.8 16 11 9 32.6 14.0 16 11 10 38.4 15.0 16 11 11 208.1 13.5 16 11 13 32.4 14.1 16 11 14 123.0 6.4 16 11 15 101.3 8.7 16 11 16 122.0 8.5 16 11 17 141.6 8.7 16 11 18 64.5 14.3 16 11 19 48.5 17.6 16 12 0 146.5 4.3 16 12 1 189.8 4.0 16 12 2 226.6 6.2 16 12 3 153.2 5.3 16 12 4 46.0 10.0 16 12 5 204.0 4.8 16 12 6 46.7 15.0 16 12 7 150.9 5.6 16 12 8 67.7 13.5 16 12 9 45.5 14.2 16 12 10 20.2 10.1 16 12 11 279.1 10.9 16 12 13 55.9 15.3 16 12 14 25.5 12.2 16 12 15 69.0 12.6 16 12 16 137.8 7.4 16 12 17 30.9 14.7 16 12 18 28.9 13.7 16 12 19 25.3 12.2 16 13 0 80.0 7.2 16 13 1 37.4 12.8 16 13 2 106.7 6.3 16 13 3 145.9 4.2 16 13 4 47.2 13.8 16 13 5 34.8 12.5 16 13 7 66.0 10.9 16 13 8 33.9 14.2 16 13 9 32.3 13.4 16 13 10 408.6 14.8 16 13 12 32.9 13.6 16 13 13 69.2 11.5 16 13 14 53.8 16.6 16 13 15 61.9 16.1 16 13 16 73.0 13.9 16 13 17 171.0 7.3 16 13 18 36.3 16.0 16 13 19 87.4 13.0 16 14 0 27.9 11.8 16 14 1 98.4 5.6 16 14 2 126.4 16 14 3 69.7 7.7 16 14 4 35.4 12.6 16 14 5 140.7 5.7 16 14 6 190.5 6.6 16 14 7 84.9 8.1 16 14 9 267.3 30.7 16 14 10 42.8 19.2 16 14 11 18.4 9.3 16 14 12 23.5 11.2 16 14 13 45.3 17.3 16 14 14 92.7 10.0 16 14 15 207.4 6.3 16 14 16 125.9 8.3 16 14 17 45.3 15.2 16 14 18 70.6 15.3 16 15 0 253.8 5.1 16 15 1 78.9 8.1 16 15 2 30.4 12.2 16 15 3 127.0 4.6 16 15 4 125.5 16 15 5 106.8 6.4 16 15 6 137.2 5.1 16 15 7 71.0 11.4 16 15 8 198.0 17.7 16 15 10 142.8 8.8 16 15 11 83.4 16 15 12 79.0 8.2 16 15 13 131.9 6.7 16 15 14 35.7 14.4 16 15 15 97.0 10.9 16 15 16 44.4 16.7 16 15 17 81.9 11.5 16 15 18 47.2 17.5 16 16 0 112.0 4.2 16 16 1 122.7 4.6 16 16 2 39.0 15.2 16 16 3 151.3 7.2 16 16 4 39.6 16.5 1L6 16 5 155.6 16 16 7 244.0 15.9 16 16 9 50.1 17.7 16 16 10 124.9 16 16 11 154.7 16 16 12 17.3 8.8 16 16 13 136.0 7.1 16 16 14 255.7 6.7 16 16 15 47.8 15.9 16 16 16 48.5 15.9 16 16 17 136.0 7.3 16 17 0 92.5 6.2 16 17 1 169.6 3.9 16 17 2 64.1 16 17 3 213.1 4.1 16 17 4 18.8 9.4 16 17 5 41.7 12.5 16 17 6 365.1 12.5 16 17 7 67.1 19.0 16 17 8 113.4 11.6 16 17 9 86.5 8.7 16 17 10 127.9 16 17 11 69.7 16.4 16 17 12 51.1 16.2 16 17 13 58.2 15.7 16 17 14 132.0 16 17 15 30.5 14.1 16 17 16 98.0 10.4 16 17 17 60.2 16.5 16 18 0 17.6 *8.7 16 18 3 25.1 11.4 16 18 4 274.3 12.4 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -157- 16 18 16 18 16 18 16 18 16 18 16 18 16 18 16 18 16 18 16 18 16 18 16 18 16 19 16 19 16 19 16 19 16 19 16 19 16 .19 16 19 16 19 16 19 16 19 16 19 16 19 16 19 16 19 16 19 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 20 16 21 16 21 16 21 16 21 16 21 16 21 16 21 16 -21 16 21 16 21 16 21 16 21 16 21 16 21 16 21 16 22 16 22 16 22 16 22 16 22 16 22 16 22 16 22 16 22' 16 2, 16 2' 16 2 16 2 5 355.2 6 73.9 1 7 17.6 8 93.2 9 59.6 1 10 183.8 11 93.4 12 57.0 13 123.6 14 183.2 15 30.7 16 106.8 0 103.2 1 221.2 2 252.1 3 155.0 4 21.9 1 5 67.3 6 65 7 76.1 1 8 77.5 9 25.3 10 108.3 11 30.5 12 71.9 13 53.0 14 150.1 15 74.5 0 133.6 1 88.3 2 83.6 3 14.6 4 19.6 5 54.3 6 109.5 7 66.8 8 37.9 9 144.4 10 146.6 11 179.2 12 110.7 13 81.0 14 24.6 15 23.6 0 120.7 1 118.9 2 103.9 3 71.5 4 56.9 5 64.0 6 51.8 7 119.5 8 15.3 9 92.4 10 111.6 11 66.8 12 25.2 13 99.9 14 39.8 0 144.1 1 17.9 2 56.6 3 66.6 4 153.0 5 72.4 6 106.5 17 33.9 8 150.4 19 151.5 110 74.8 1 1 84.6 Z~ 12 17.5 20.7 8.4 8.8 9.4 1.3 5.0 8.3 13.0 10.6 6.4 14.1 7.9 13.8 10.0 13.1 21.4 11.1 8.5 8.8 10.3 8.9 11.5 9.3 13.2 10.7 14.8 6.4 13.3 7.6 6.4 8.2 7.3 9.8 9.0 11.2 14.5 15.2 6.3 8.2 9.0 9.2 9.1 11.7 11.6 6.1 9.6 5.4 6.7 8.2 7.4 9.4 7.6 7.8 7.8 7.8 9.5 11.9 10.7 16.5 4.2 8.7 8.6 10.6 5.6 8.7 5.3 13.9 6.0 6.8 9.9 8.2 8.9 16 22 13 92.5 8.5 16 23 0 87.4 7.1 16 23 1 83.5 12.7 16 23 2 72.6 9.5 16 23 3 173.5 5.0 16 23 4 90.4 6.8 16 23 5 154.8 4.8 16 23 6 37.0 15.1 16 23 7 35.7 13.4 16 23 8 95.1 7.8 16 23 9 103.4 9.8 16 23 10 186.7 5.5 16 23 11 72.5 13.2 16 23 12 79.4 11.9 16 24 0 140.8 4.0 16 24 1 17.5 8.8 16 24 2 121.8 6.3 16 24 3 62.6 17.2 16 24 4 80.2 11.2 16 24 5 86.7 7.7 16 24 6 27.6 12.3 16 24 7 118.9 5.0 16 24 8 79.5 11.2 16 24 9 68.6 14.3 16 24 10 55.4 14.3 16 24 11 19.8 10.0 16 25 0 130.6 6.2 16 25 1 211.5 6.7 16 25 2 80.8 9.0 16 25 3 51.7 9.6 16 25 4 130.2 4.9 16 25 5 37.5 12.9 16 25 6 68.4 6.8 16 25 7 31.1 11.9 16 25 8 21.3 10.1 16 25 9 47.3 17.2 16 25 10 34.5 16.8 16 26 1 29.7 11.4 16 26 2 102.5 5.9 16 26 3 65.5 8.4 16 26 4 124.8 6.5 16 26 5 25.1 11.6 16 26 6 71.0 8.3 16 26 7 47.5 17.5 16 26 8 60.0 17.3 16 27 0 69.5 7.2 16 27 1 100.2 8.3 16 27 2 107.4 10.8 16 27 3 23.9 10.8 16 27 4 43.1 12.7 16 27 5 73.9 6.6 16 27 6 24.2 11.4 16 28 0 31.6 14.5 16 28 1 57.5 7.8 16 28 2 113.8 5.5 16 28 3 41.9 15.0 16 28 4 116.1 17.3 17 0 0 125.7 13.0 17 0 2 106.8 7.8 17 0 3 128.5 7.6 17 0 4 21.2 14.4 17 0 5 25.2 16.7 17 0 6 251.8 8.1 17 0 7 20.9 14.7 17 0 8 165.2 7.9 17 0 9 96.3 16.5 17 0 10 42.8 26.2 17 0 11 488.1 14.6 17 0 13 15.5 11.5 17 0 14 48.3 25.5 17 0 15 107.2 18.7 17 0 16 183.8 10.3 0 17 165.7 11.0 0 18 107.8 24.7 0 19 35.7 22.9 1 0 67.5 15.3 1 1 50.0 16.2 1 2 70.2 7.8 1 3 32.4 13.0 1 4 72.3 8.0 1 5 63.8 15.8 1 6 153.5 9.6 1 7 44.0 14.8 1 8 53.6 13.0 1 9 144.2 8.6 1 10 30.0 14.9 1 11 316.3 10.6 1 13 32.4 13.6 1 14 120.8 9.6 1 15 80.6 15.1 1 16 112.7 9.7 1 18 102.3 14.5 2 0 170.5 6.2 2 1 73.9 11.5 2 2 203.9 5.1 2 3 139.1 4.5 2 4 172.2 4.3 2 5 152.4 6.6 2 6 156.1 6.0 2 7 106.4 7.0 2 8 122.8 6.1 2 11 334.7 8.3 2 12 26.3 13.0 2 13 71.1 10.9 2 14 67.5 16.0 2 15 52.2 19.8 2 16 141.3 7.4 2 17 136.4 8.1 2 18 32.6 15.0 2 19 138.6 8.3 3 0 107.5 6.5 3 1 26.5 12.1 3 2 122.1 4.8 3 3 140.3 5.2 3 4 139.1 6.0 3 5 127.7 5.9 3 6 21.2 10.5 3 8 117.2 6.2 3 9 31.6 14.7 3 11 301.4 10.9 3 12 21.1 10.5 3 13 100.3 10.3 3 14 61.6 17.4 3 15 62.6 16.2 3 16 151.7 8.4 3 17 36.1 14.7 3 18 39.3 16.5 3 19 154.7 8.3 4 0 86.2 6.4 4 1 38.5 11.9 4 2 166.1 4.8 4 3 32.0 13.4 4 4 45.7 17.5 4 5 72.7 9.7 4 6 140.2 8.2 4 7 105.3 7.8 4 8 148.9 5.5 4 9 73.7 17.2 4 10 89.6 19.4 4 11 252.8 13.9 4 12 28.5 13.0 4 13 22.4 11.1 14 14 35.3 16.6 4 15 41.0 16.5 17 4 17 4 17 4 17 4 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 5 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 6 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 7 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 17 8 16 179.6 17 176.8 18 151.5 19 72.5 1 0 49.4 1 1 166.0 2 33.9 1 3 42.0 1 4 231.4 5 83.8 6 69.0 7 105.4 8 87.0 1 9 117.4 10 237.2 12 87.8 13 20.5 1 14 132.9 16 124.2 17 81.7 18 37.2 19 33.9 0 94.4 2 25.5 1 3 102.6 4 118.6 5 56.1 1 6 87.1 7 127.9 8 145.7 10 298.6 12 76.7 13 35.5 14 72.8 15 186.0 16 101.9 17 185.2 18 93.1 19 141.7 0 143.4 1 55.0 1 2 26.7 1 3 142.8 4 47.3 1 5 99.6 6 84.9 1 7 42.21 8 .29.0 10 297.7 11 27.0 12 47.3 13 135.8 14 93.8 15 84.3 17 26.4 18 125.7 0 134.0 1 120.3 2 46.6 3 101.8 4 74.4 5 158.2 6 120.1 7 71.2 8 20.5 9 318.3 11 75.0 12 105.1 13 107.6 114 109.7 115 164.0 116 67.1 6.7 4.9 1.6 4.1 3.2 2.7 7.2 0.0 8.7 16.9 9.2 10.3 7.4 8.9 10.9 15.5 15.7 1.4 5.9 4.9 0.1 8.1 10.7 11.2 14.8 14.6 9.7 6.8 10.8 3.9 .1.7 4.3 .0.8 10.0 14.9 12.8 14.1 12.8 15.1 7.1 10.9 15.9 12.9 10.9 8.3 9.9 4.4 8.8 11.4 10.2 11.6 10.9 7.9 7.4 8.3 8.1 17.7 SUBSTITUTE SHEET (RULE 26) WO 99/10379 -158- 17 8 17 108.1 8.2 17 8 18 58.5 17.2 17 9 0 114.9 4.8 17 9 I 148.5 4.2 17 9 2 25.2 11.4 17 9 3 170.4 5.1 17 9 4 168.3 8.0 17 9 5 104.5 6.7 17 9 6 58.3 15.0 17 9 7 166.0 5.9 17 9 9 435.4 15.3 17 9 10 21.8 10.9 17 9 11 115.3 9.0 17 9 12 106.1 8.8 17 9 13 43.0 16.5 17 9 14 61.1 15.1 17 9 15 244.9 8.8 17 9 16 80.0 17.4 17 9 17 26.0 12.5 17 9 18 42.6 16.1 17 10 0 78.7 7.2 17 10 1 157.3 4.9 17 10 2 125.8 9.7 17 10 3 237.7 6.9 17 10 4 107.2 6.5 17 10 5 142.5 9.4 17 10 6 29.2 14.1 17 10 7 22.9 11.2 17 10 8 414.7 14.3 17 10 10 45.6 15.4 17 10 11 34.7 15.4 17 10 12 57.5 17.0 17 10 13 76.3 17.0 17 10 14 153.4 6.2 17 10 16 23.9 11.9 17 10 17 83.5 12.4 17 10 18 103.4 14.5 17 11 0 26.5 12.2 17 11 1 44.6 12.8 17 11 2 125.3 6.7 17 11 3 99.2 6.9 17 11 4 62.7 8.2 17 11 5 15.8 7.9 17 11 6 36.1 13.7 17 11 7 252.4 14.9 17 11 8 175.2 11.5 17 11 9 36.3 14.2 17 11 10 38.1 15.7 17 11 11 140.2 6.1 17 11 12 44.1 15.1 17 11 13 32.0 15.1 17 41 14 147.8 7.1 17 11 15 80.5 10.7 17 11 16 40.6 17.1 17 11 17 89.1 12.8 17 12 0 155.6 7.7 17 12 1 21.8 10.4 17 12 2 99.4 5.8 17 12 3 66.1 8.0 17 12 4 20.0 9.9 17 12 5 114.7 6.6 17 12 6 116.1 9.6 17 12 7 272.4 12.9 17 12 9 38.5 16.2 17 12 10 32.6 13.8 17 12 11 42.6 14.4 17 12 12 26.4 12.4 17 12 13 169.2 18.8 17 12 14 34.0 15.9 17 12 15 111.4 9.9 17 12 16 44.5 18.2 17 12 17 61.5 19.0 17 13 0 147.2 6.1 17 13 1 216.5 4.6 17 13 2 142.8 4.5 17 13 3 159.4 4.7 17 13 5 291.4 14.7 17 13 6 367.7 15.6 17 13 8 53.1 15.0 17 13 9 119.6 8.7 17 13 10 131.3 6.9 17 13 11 44.1 15.4 17 13 12 199.9 6.8 17 13 13 136.5 7.0 17 13 14 33.3 15.0 17 13 15 157.9 7.0 17 13 16,102.6 10.3 17 14 0 75.3 7.2 17 14 1 58.8 9.2 17 14 3 67.4 16.7 17 14 4 383.3 14.7 17 14 5 201.0 11.5 17 14 7 88.2 7.7 17 14 8 57.7 14.6 17 14 9 76.3 11.7 17 14 10 39.3 14.5 17 14 11 57.0 17.4 17 14 12 105.5 10.3 17 14 13 178.0 8.1 17 14 14 29.0 12.9 17 14 I5 74.7 14.1 17 14 16 93.6 10.3 17 15 0 45.8 19.3 17 15 1 178.7 12.7 17 15 2 449.6 12.9 17 15 3 217.7 15.2 17 15 4 84.4 11.4 17 15 5 15.2 7.6 17 15 6 97.3 7.3 17 15 7 89.4 9.9 17 15 8 85.4 9.6 17 15 9 146.7 6.1 17 15 10 54.6 14.8 17 15 11 152.2 6-3 17 15 12 93.4 11.4 17 15 13 181.5 7.3 17 15 14 87.2 9.8 17 15 15 134.6 8.0 17 16 0 266.0 16.7 17 16 1 115.2 8.7 17 16 2 24.2 12.1 17 16 5 166.6 7.6 17 16 6 215.6 4.6 17 16 7 56.3 15.7 17 16 8 38.3 14.0 17 16 9 72.1 11.9 17 16 10 20.0 10.0 17 16 11 122.7 7.4 17 16 13 65.3 13.5 17 16 14 29.6 13.5 17 16 15 21.9 10.8 17 17 1 84.0 6.6 17 17 2 87.3 8.2 17 17 3 100.7 8.5 17 17 4 21.2 10.4 17 17 5 67.9 8.3 17 17 6 137.0 4.6 17 17 7 95.1 6.3 17 17 8 98.3 7.6 17 17 9 23.4 11.4 17 17 10 98.0 11.3 17 17 11 17.7 8.9 17 17 12 72.5 14.7 17 17 13 77.2 11.5 17 17 14 180.9 6.3 17 18 0 135.3 5.2 17 18 I 65.4 9.3 17 18 2 65.1 7.4 17 18 3 150.2 4.5 17 18 4 135.4 4.6 17 18 5 142.2 5.7 17 18 6 37.3 14.1 17 18 7 122.8 7.2 17 18 9 124.0 7.1 17 18 10 79.9 10.7 17 18 11 48.9 19.4 17 18 12 89.3 12.0 17 18 13 61.2 14.7 17 19 0 94.4 6.2 17 19 1 37.0 14.6 17 19 2 25.2 11.2 17 19 3 66.8 19.3 17 19 4 109.8 11.7 17 19 5 55.0 18.9 17 19 6 112.4 7.2 17 19 7 115.4 11.8 17 19 8 198.7 8.2 17 19 9 22.9 11.2 17 19 10 116.8 10.4 17 19 11 34.9 15.2 17 19 12 113.0 7.6 17 19 13 33.3 13.9 17 20 0 138.6 9.1 17 20 1 59.3 13.0 17 20 2 171.1 5.3 17 20 3 31.6 13.9 17 20 4 99.7 6.2 17 20 5 32.4 13.4 17 20 6 135.8 5.5 17 20 7 156.6 7.6 17 20 8 24.6 11.4 17 20 9 24.6 12.1 17 20 10 70.1 10.6 17 20 11 39.5 15.8 17 20 12 74.0 16-.0 17 21 0 138.0 5.5 17 21 1 69.6 7.8 17 21 2 235.3 4.9 17 21 3 71.1 7.7 17 21 4 93.6 6.6 17 21 5 184.0 8.4 17 21 6 77.9 10.4 17 21 7 64.3 8.4 17 21 8 177.0 9.0 17 21 9 37.4 15.4 17 21 10 100.7 8.0 17 22 0 174.4 7.5 17 22 1 191.5 7.3 17 22 2 178.6 7.6 17 22 3 167.5 8.5 17 22 4 60.7 19.6 17 22 5 83.1 14.9 17 22 6 30.3 13.3 17 22 7 95.7 11.5 17 22 8 90.5 14.3 17 22 9 50.8 14.9 17 22 10 26.7 13.5 17 23 0 113.6 5.1 17 23 2 113.2 6.2 17 23 3 80.1 7.0 17 23 4 97.0 5.4 17 23 5 59.8 8.3 17 23 6 49.4 12.0 17 23 7 178.2 5.8 17 23 8 29.8 13.9 17 24 1 83.3 13.2 PCT/GB98/02542 17 24 2 92.9 8.7 17 24 3 100.3 12.9 17 24 4 50.1 19.2 17 24 5 54.7 13.0 17 24 6 84.1 11.8 17 24 7 65.4 9.8 17 25 0 80.4 9.2 17 25 1 16.3 8.1 17 25 2 65.2 17 25 3 69.4 9.7 17 25 4 35.0 12.8 17 25 5 53.3 16.9 17 26 0 33.0 14.2 17 26 1 31.4 14.2 17 26 2 161.7 36.4 18 0 0 17.0 11.8 18 0 I 101.1 15.7 18 0 2 182.7 12.9 18 0 3 129.0 26.1 18 0 4 29.3 21.1 18 0 6 312.8 30.8 18 0 7 361.4 10.3 18 0 9 71.4 19.1 18 0 10 15.9 11.9 18 0 11 45.4 23.5 18 0 12 171.7 12.3 18 0 13 125.6 13.4 18 0 14 52.1 25.4 18 0 15 21.7 15.4 18 0 16 73.6 24.2 18 1 0 141.8 4.3 18 1 1 164.8 6.6 18 1 2 45.8 15.1 18 1 3 99.6 21.9 18 1 4 36.8 17.8 18 I 6 262.8 18.6 18 1 7 360.2 10.9 18 1 9 67.5 12.1 18 1 10 165.6 18 1 11 79.0 12.4 18 1 12 158.1 6.9 18 1 13 73.8 14.8 18 1 14 39.4 16.0 18 1 15 76.1 11.8 18 1 16 119.6 8.7 18 I 17 40.9 16.1 18 2 0 70.8 7.1 18 2 1 145.3 18 2 2 202.8 7.6 18 2 3 87.1 24.9 18 2 4 45.1 15.9 18 2 5 112.6 12.7 18 2 6 371.4 25.6 18 2 7 387.0 17.0 18 2 9 60.2 15.3 18 2 10 106.1 10.2 18 2 11 83.6 11.5 18 2 12 20.1 10.1 18 2 13 131.4 18 2 14 50.4 16.9 18 2 15 28.6 13.3 18 2 16 86.6 12.3 18 2 17 22.8 11.4 18 3 0 136.7 6.2 18 3 1 121.7 6.8 18 3 2 91.1 9.6 18 3 3 70.9 25.4 18 3 4 100.0 12.8 18 3 5 20.2 10.2 18 3 6 409.5 15.9 18 3 7 285.7 15.1 18 3 9 38.5 15.1 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -159- 87.2 11.6 11 120.0 7.5 12 75.2 12.0 13 111.3 9.7 W4 25.8 12.7 28.7 13.4 16 80.0 15.4 17 32.5 14.7 0 51.6 11.9 1 105.5 8.5 2 143.1 16.5 3 39.8 18.9 4 88.2 9.3 1 33.5 6.1 6 398.3 12.3 7 247.5 22.8 8 64.1 13.5 9 136.2 6.4 51.1 18.9 11 111.7 8.5 12 106.3 11.1 13 161.1 7.0 14 38.0 16.7 28.5 13.4 16 97.2 9.8 17 96.9 11.5 0 133.5 7.6 1 63.0 18.1 2 155.7 17.3 3 37.1 14.8 4 50.9 14.2 115.9 12.2 6 156.0 7.5 7 45.0 18.7 8 29.5 13.2 9 78.2 9.9 198.2 8.9 H1 7710 16.2 12 28.3 14.0 13 126.0 8.1 14 98.0 11.7 16 86.3 12.8 0 248.3 5.6 1 26.3 12.7 2 149.3 4.6 3 173.5 5.4 4 124.5 9.3 242.4 12.2 6 174.3 5.2 7 91.1 13.4 8 144.0 5.7 9 56.1 15.6 159.1 6.7 11 115.9 10.6 12 101.3 9.8 13 119.8 9.2 14 28.7 13.5 35.7 16.3 16 111.5 9.7 0 64.5 9.3 1 99.2 6.5 3 36.2 13.9 4 185.2 9.4 308.5 15.8 7 34.7 14.7 8 51.7 13.9 9 30.9 14.0 98.7 10.8 11 83.5 12.3 12 29.0 13.9 13 186.1 7.1 14 87.0 10.7 18 7 15 30.1 13.8 18 7 16 39.3 16.3 18 8 0 15.2 7.7 18 8 1 13 3. 1 7.9 18 8 2 67.5 9.4 18 8 3 266.6 20.1 18 8 4 360.8 13.3 18 8 5 19.2 9.7 18 8 6 32.1 13.9 18 8 7 86.5 10.4 18 8 8 94.0 9.1 18 8 9 135.3 6.4 18 8 10 122.0 8.1 18 8 11 28.5 13.3 18 8 12 235.4 5.3 18 8 13 83.8 13.2 18 8 14 62.2 12.4 18 8 15 112.3 10.6 18 8 16 34.8 15.5 18 9 1 95.2 12.5 18 9 2 332.6 14.7 18 9 3 448.4 14.4 18 9 4 62.2 24.4 18 9 5 20.9 10.6 18 9 6 55.4 13.4 18 9 7 26.8 12.7 18 9 8 100.6 12.1 18 9 9 94.5- 9.7 18 9 10 89.3 13.1 18 9 11 33.1 14.3 18 9 12 249.2 8.4 18 9 13 92.9 12.8 18 9 14 34.3 13.9 18 9 15 48.8 15.3 18 10 0 311.7 11.0 18 10 1 349.2 10.0 18 10 2 263.7 9.6 18 10 3 155.0 9.8 18 10 5 134.3 6.6 18 10 6 63.1 8.5 18 10 8 192.0 6.1 18 10 9 71.4 14.6 18 10 10 135.9 9.0 18 10 11 148.3 7.4 18 10 12 149.8 7.5 18 10 13 57.4 15.7 18 10 14 147.3 11.9 18 11 0 254.6 11.3 18 11 1 99.5 9.5 18 11 2 22.6 10.9 18 11 3 113.5 5.6 18 11 4 177.2 4.6 18 11 5 18.2 9.1 18 11 6 108.0 5.9 18 11 7 111.6 8.3 18 11 8 137.3 8.6 18 11 9 91.7 12.6 18 11 10 60.7 19.7 18 11 11 361.6 17.9 18 11 12 69.6 14.5 18 11 14 30.6 13.5 18 11 15 25.8 12.7 18 12 1 114.8 5.6 18 12 2 144.6 5.9 18 12 3 20.9 10.2 18 12 4 45.4 14.4 18 12 5 139.6 5.6 18 12 6 29.0 12.1 18 12 7 91.4 9.8 18 12 8 91.9 8.4 18 12 9 108.0 12.3 18 12 10 193.5 9.6 18 12 11 34.5 15.7 18 12 12 23.3 11.5 18 12 13 87.7 10.0 18 12 14 58.0 17.2 18 13 0 50.8 13.9 18 13 1 102.0 8.2 18 13 2 28.5 12.3 18 13 3 112.2 6.7 18 13 4 133.4 7.2 18 13 5 106.1 6.3 18 13 6 31.2 13.9 18 13 7 54.2 13.0 18 13 8 71.0 13.1 18 13 9 70.5 16.8 18 13 10 41.0 17.5 18 13 11 36.4 15.5 18 13 12 26.8 13.4 18 13 14 21.3 10.6 18 14 0 159.2 6.6 18 14 1 72.6 13.8 18 14 2 80.8 9.2 18 14 3 130.0 6.7 18 14 4 66.2 12.1 18 14 5 59.9 9.3 18 14 6 85.1 8.6 18 14 7 148.6 6.5 18 14 8 138.4 6.9 18 14 9 80.6 12.4 18 14 10 40.4 17.5 18 14 11 46.9 15.4 18 14 12 35.6 16.2 18 14 13 79.1 14.1 18 15 0 59.9 12.4 18 15 1 89.4 8.5 18 15 2 134.9 5.9 18 15 3 34.8 16.0 18 15 4 73.3 8.1 18 15 5 88.9 7.5 18 15 6 83.3 11.1 18 15 7 156.4 13.7 18 15 8 136.3 8.3 18 15 9 114.5 11.8 18 15 10 29.1 13.8 18 15 11 112.3 9.2 18 15 12 52.0 18.5 18 15 13 124.8 9.8 18 16 0 131.6 4.5 18 16 1 22.0 10.1 18 16 2 167.2 8.3 18 16 3 151.8 5.8 18 16 4 87.4 9.2 18 16 5 137.4 7.9 18 16 6 29.9 13.0 18 16 7 421.3 59.6 18 16 8 51.1 16.1 18 16 9 136.4 8.0 18 16 10 136.3 8.3 18 16 11 83.9 13.4 18 16 12 26.7 12.7 18 17 0 121.0 6.8 18 17 1 54.2 12.7 18 17 2 106.1 12.8 18 17 3 54.4 16.5 18 17 4 95.0 10.6 18 17 5 132.6 5.8 18 17 6 186.8 10.8 18 17 7 17.1 8.6 18 17 8 127.4 11.4 18 17 9 26.7 12.5 18 17 10 18.0 9.2 18 17 11 144.7 8.6 18 18 0 153.9 5.9 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 19 18 19 18 19 18 19 18 19 18 19 18 19 18 19 18 19 18 19 18 20 18 20 18 20 18 20 18 20 18 20 18 20 18 20 18 20 18 21 18 21 18 21 18 21 18 21 18 21 18 21 18 21 18 22 18 22 18 22 18 22 18 22 18 22 18 23 18 23 18 23 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 0 19 1 19 1 19 1 19 1 19 1 19 1 19 1 19 1 19 1 19 1 19 1 1 120.7 2 106.7 7.6 3 113.7 9.1 4 106.1 5.7 5 84.4 7.8 6 51.1 11.6 7 23.8 10.7 8 101.8 9.4 9 64.0 15.2 10 26.5 13.2 0 90.0 9.3 1 78.6 2 124.6 7.1 3 63.0 23.5 4 247.2 6.1 5 29.2 14.4 6 100.7 15.3 7 49.8 12.8 8 27.9 12.4 9 67.5 13.3 0 29.8 13.0 1 47.8 15.3 2 151.0 8.4 3 116.4 4 158.9 6.6 5 123 .6 10.5 6 31.2 12.1 7 82.9 9.2 8 25.5 12.8 0 75.5 11.9 1 166.9 2 54.4 14.5 3 68.6 11.1 4 42.8 12.5 5 18.7 9.2 6 74.5 8.1 7 48.8 13.9 0 124.9 5.3 1 78.1 8.1 2 136.2 6.4 3 20.0 10.0 4 98.9 14.5 5 44.4 18.9 0 25.9 12.0 1 109.9 6.1 3 79.2 17.3 0 14.9 11.0 1 12.0 2 24.4 15.3 3 76.5 35.1 4 86.1 35.0 5 129.9 7.7 6 203.9 7. 3 7 22.9 16.7 8 67.5 21.5 9 108.2 18.4 10 117.8 15.1 11 194.2 15.8 12 63 .2 21.8 13 125 .8 12.2 14 85 .1 25.1 0 101.1 7.4 1 77.7 8.2 2 109.6 5.7 3 33.2 16.4 4 86.5 20.4 5 147.0 11.6 6 50.9 16.2 7 55.2 19.2 8 115.5 7.9 9 122.0 11.5 10 139.6 7.8 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 -160- 11 52.2 20.6 12 51.2 16.0 13 111.2 10.7 14 38.8 16.5 0 18.9 9.4 1 43.1 15.5 2 80.4 9.7 3 83.7 12.3 4 135.3 14.0 59.9 9.5 6 105.6 6.5 7 72.1 19.4 8 98.7 9.0 9 68.4 16.2 131.4 8.8 11 30.1 15.1 12 28.4 13.8 13 70.1 15.9 0 34.8 13.0 1 51.1 15.8 2 30.8 13.4 3 129.9 8.3 4 33.4 13.2 74.3 7.7 6 40.0 13.7 7 241.7 9.3 8 164.3 6.1 9 136.9 8.2 214.1 10.5 11 45.5 18.5 12 88.3 11.4 13 128.8 8.9 14 44.5 17.0 0 69.3 8.1 1 150.4 4.8 2 153.0 9.0 3 119.8 9.1 4 32.9 14.6 17.0 8.5 6 103.3 6.8 7 133.9 12.7 8 86.6 10.3 9 142.0 7.8 93.1 12.6 11 23.3 11.6 12 47.7 16.6 13 115.2 8.1 14 23.3 11.6 0 152.1 5.9 1 61.2 9.5 2 168.8 5.8 3 77.1 14.8 4 94.4 8.4 134.8 5.7 6 100.2 7.9 7 105.5 14.6 8 122.4 10.6 9 168.2 8.4 171.1 7.6 11 35.7 17.3 12 64.5 15.2 13 53.5 17.1 14 146.3 8.4 0 101.9 7.9 1 37.4 13.7 2 65.9 13.6 3 122.5 14.7 4 74.8 9.3 32.9 13.8 6 111.9 8.4 7 61.7 13.8 8 78.9 13.0 19 6 9 170.9 6.7 19 6 10 130.5 12.1 19 6 11 97.4 10.7 19 6 12 47.0 20.1 19 6 13 39.3 16.5 19 7 0 112.2 6.3 19 7 1 91.4 7.4 19 7 2 55.3 19.9 19 7 3 117.8 8.8 19 7 4 129.3 7.7 19 7 5 111.3 13.3 19 7 6 55.5 20.8 19 7 7 59.0 14.5 19 7 8 27.5 13.3 19 7 9 137.2 9.6 19 7 10 26.2 13.0 19 7 11 72.7 16.8 19 7 12 28.2 13.7 19 7 13 25.4 12.6 19 8 0 134.6 8.8 19 8 1 35.3 14.8 19 8 2 74.4 13.4 19 8 3 35.8 14.3 19 8 4 42.3 13.8 19 8 5 63.9 12.2 19 8 6 40.1 14.0 19 8 7 21.2 10.5 19 8 8 165.1 7.6 19 8 9 178.9 7.2 19 8 10 68.7 15.0 19 8 11 44.1 18.7 19 8 12 34.3 15.7 19 8 13 21.5 10.9 19 9 0 47.6 16.9 19 9 1 35.6 13.8 19 9 2 83.8 8.5 19 9 3 116.1 6.4 19 9 4 49.9 14.5 19 9 5 118.3 12.5 19 9 7 75.8 11.6 19 9 8 110.8 11.2 19 9 9 75.0 10.9 19 9 10 115.4 11.5 19 9 11 97.9 11.6 19 9 12 115.4 8.7 19 10 0 39.3 14.0 19 10 1 180.4 4.8 19 10 2 93.4 6.4 19 10 3 44.5 13.9 19 10 4 47.1 14.5 19 10 5 81.6 27.1 19 10 6 113.5 8.5 19 10 7 275.8 8.3 19 10 8 74.5 21.5 19 10 10 147.5 7.5 19 10 11 45.1 16.8 19 10 12 121.6 9.4 19 12 3 149.8 7.3 19 12 4 95.8 7.6 19 12 5 182.6 6.1 19 12 6 67.1 12.2 19 12 7 28.0 12.8 19 12 8 106.1 10.5 19 12 9 96 .9 9.9 19 12 10 26.6 13.3 19 12 11 20.8 10.4 19 13 0 17.0 8.6 19 13 1 90.2 9.7 19 13 2 24.7 11.9 19 13 3 126.1 7.4 19 13 4 232.0 8.7 19 13 5 29.6 13.5 19 13 6 30.1 12.6 19 13 7 71.6 17.8 19 13 8 42 .7 15.8 19 13 9 33.3 14.9 19 13 10 127.2 14.4 19 14 0 42.2 14.0 19 14 1 190.0 5.0 19 14 2 115.7 6.1 19 14 3 167.1 8.4 19 14 4 158.4 9.0 19 14 5 142.8 7.2 19 14 6 131.2 13.0 19 14 7 69.0 11.3 19 14 8 67.3 13.9 19 14 9 29.1 13.7 19 14 10 31.7 14.8 19 15 0 153.8 9.6 19 15 1 202.0 7.9 19 15 2 152.2 8.2 19 15 3 29.5 13.3 19 15 4 154.6 5.2 19 15 5 135.3 12.0 19 15 6 147.5 9.4 19 15 7 163.7 10.8 19 15 8 31.4 13.5 19 15 9 22.5 11.3 19 16 0 39.9 15.5 19 16 1 18.6 9.4 19 16 2 80.9 10.9 19 16 3 38.1 14.5 19 16 4 23.9 11.6 19 16 5 61.8 13.2 19 16 6 142.1 10.8 19 16 7 77.2 9.5 19 16 8 57.3 15.2 19 17 0 97.2 9.1 19 17 1 30.0 12.6 19 17 2 80.2 9.7 t9 17 3 256.9 6.1 19 17 4 161.2 11.2 19 17 5 21.2 10.3 19 17 6 76.2 8.4 19 17 7 101.5 20.3 19 18 0 157.5 9.8 19 18 1 158.2 11.1 19 18 2 38.3 14.5 19 18 3 110.4 9.0 19 18 4 39.7 14.5 19 18 5 37.0 13.2 19 18 6 70.3 15.7 19 19 0 99.8 8.0 19 19 2 19.9 9.9 19 19 3 137.3 6.5 19 19 4 43.5 16.3 19 20 0 18.0 9.1 19 20 1 24.1 12.1 20 0 0 47.9 30.0 PCT/GB98/02542 )0 1 40.1 26.9 )0 2 66.5 14.7 )0 3 113.4 9.4 )0 4 162.5 )0 5 237.2 14.2 )0 6 153.5 20.4 )0 7 65.9 22.0 )0 8 99.7 16.8 )0 9 88.6 22.8 )0 10 42.5 26.1 0 11 29.3 19.1 1 0 82.4 21.4 1 1 67.8 14.0 1 2 43.0 13.6 1 3 25.2 12.0 )1 4 155.6 6.2 )1 5 57.8 14.8 )1 6 88.2 12.2 )1 7 24.0 12.0 1 8 63.4 14.1 0 1 9 50.3 18.5 0 1 10 33.6 15.7 D 11I 39.5 17.3 D 2 0 48.4 21.0 D 2 1 54.3 17.9 O 2 2 21.0 10.1 D 2 3 191.7 6.8 D 2 4 119.8 7.7 D 2 5 74.1 14.2 D 2 6 32.9 15.4 D 2 7 50.0 17.7 0 2 8 37.1 16.4 0 2 9 62.3 18.7 0 2 10 70.2 18.1 0 2 11 54.3 21.7 0 3 0 37.4 18.4 0 3 1 142.6 0 3 2 88.3 7.9 0 3 3 143.8 8.7 0 3 4 224.7 8.1 0 3 5 137.8 11.9 0 3 6 249.5 10.5 0 3 7 51.4 17.5 0 3 8 152.4 8.4 0 3 9 40.5 16.9 0 3 10 53.8 22.0 0 4 0 111.7 10.1 0 4 1 71.7 11.4 .0 4 2 69.9 9.1 ,0 4 3 188.7 5.6 .0 4 4 71.6 15.1 '0 4 5 67.1 12.0 .0 4 6 36.5 17.6 :0 4 7 61.4 21.6 0 4 8 83.4 12.5 0O 4 9 56.7 18.2 !0 5 0 48.0 16.2 !0 5 1 142.7 11.4 !0 5 2 162.2 10.5 0 5 3 224.0 11.0 !0 5 4 114.0 14.0 T0 5 5 80.8 13.4 !0 5 6 159.8 10.9 W0 5 7 93.2 9.9 !0 5 8 56.8 16.7 W0 5 9 55.9 16.5 !0 5 10 28.6 13.9 Z0 6 0 93.0 8.4 0 6 1 85.5 Z0 6 2 73.1 10.7 20 6 3 146.9 7.9 20 6 4 48.7 13.4 19 11 19 1I 19 11 19 11 19 11 19 11 19 11 19 11 19 11 19 11 19 1l 19 11 19 12 19 12 19 12 67.0 46.6 46.1 158.6 47.4 35.8 86.8 155.3 127.4 30.9 31.1 28.2 19.5 28.4 67.6 13.0 13.0 16.5 6.3 13.2 13.8 9.3 11.4 9.3 14.1 15.1 14.2 9.8 14.2 13.6 SUBSTITUTE SHEET (RULE WO 99/10379 6 5 25.4 12.8 20 15 3 36.6 15.4 6 6 38.3 14.4 20 16 0 50.7 17.6 6 7 38.7 15.6 21 0 0 135.7 7.8 6 8 65.7 20.8 21 0 1 133.3 17.4 6 9 36.6 15.1 21 0 2 74.5 17.5 7 0 144.2 5.8 21 0 3 158.3 24.1 7 1 188.1 7.5 21 0 4 148.2 11.7 7 2 137.2 12.6 21 0 5 70.0 18.3 7 3 151.4 12.0 21 1 0 125.7 5.7 7 4 134.4 6.1 21 1 1 113.3 8.1 7 5 38.6 15.9 21 1 2 57.5 14.1 7 6 27.1 12.3 21 1 3 60.6 13.5 7 7 70.6 10.4 21 1 4 64.3 14.4 7 8 128.5 17.6 21 1 5 28.2 12.5 8 0 105.4 6.7 21 2 0 130.6 11.0 8 1 69.1 15.2 21 2 1 85.8 10.6 8 2 185.4 16.6 21 2 2 25.1 11.9 8 3 20.6 10.1 21 2 3 19.4 9.7 8 5 99.3 15.6 21 2 4 21.3 10.6 8 6 17.3 8.8 21 2 5 54.6 15.2 8 7 73.8 11.2 21 3 0 96.9 10.5 8 8 24.7 12.2 21 3 1 f41~9 15.3* 8 9 47.3 17.5 21 3 2 64.4 15.3 9 0 113.0 7.0 21 3 3 44.5 18.3 9 1 62.0 16.4 21 3 5 37.9 16.0 9 2 82.2 10.4 21 4 0 65.6 13.6 9 3 68.4 10.4 21 4 1 80.6 10.6 9 4 23.9 11,4 21 4 2 76.7 10.9 9 5 101.2 9.4 21 4 3 53.7 18.1 9 6 32.7 14.2 21 4 4 36.5 17.2 9 7 48.0 19.6 21 4 5 42.7 17.3 9 8 39.3 14.4 21 5 0 36.6 14.9 10 0 68.1 12.6 21 5 1 66.1 13.5 10 1 83.0 17.8 21 5 3 41.1 16.5 10 2 53.0 16.4 21 5 5 38.5 16.0 10 3 92.6 15.0 21 6 0 41.7 16.8 10 4 118.9 9.0 21 6 1 22.9 11.3 10 5 51.3 15.6 21 6 2 32.1 13.3 10 6 67.3 11.1 21 6 3 76.9 17.5 10 7 41.9 16.5 21 6 4 158.1 18.5 10 8 80.6 10.5 21 7 1 86.5 17.7 11 0 210.9 5.3 21 7 2 61.9 14.1 11 1 56.8 15.2 21 7 3 64.2 17.4 11 2 42.1 16.1 21 7 4 44.0 17.8 11 3 80.6 12.1 2.1 8 0 31.0 13.3 11 4 77.6 10.2 21 8 1 50.7 12.6 11 5 97.2 14.2 21 8 2 58.5 14.5 11 6 23.4 11.0 21 9 0 112.8 6.9 11 7 22.6 11.2 21 9 1 23.5 11.2 12 0 71.3 10.7 12 1 41.4 14.6 42 2 25.2 11.7 12 3 171.2 10.7 12 4 77.8 11.9 12 5 131.0 12.7 12 6 76.2 10.1 12 7 37.1 16.5 13 0 108.0 8.8 13 1 222.7 5.3 13 2 107.3 13 3 103.8 7.9 13 4 165.7 11.2 13 5 165.4 13.6 13 6 27.9 13.9 14 0 146.0 12.4 14 1 114.1 16.2 14 2 34.9 13.2 14 3 26.4 12.2 14 4 29.2 14.2 15 0 31.1 13.5 15 1 27.1 12.7 15 2 24.2 11.8 PCT/GB98/02542 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCTIGB98/02542 -162- Table 2a.

CRYSTI

SCALEI

SCALE2 SCALD3

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ATOM

42.196 83.729 67.237 90.00 93.30 90.00 P21 0.023699 0.000000 0.001366 0.00000 0.000000 0.011943 0.000000 0.00000 0.000000 0.000000 0.0 14897 0.00000 1 GB ILE L 3 31.902 -1.191 8.768 1.0022.21 2 CG2 ILE L 3 30.875 -2.276 8.525 1.00 27.45 3 CGI ILE L 3 31.406 0.116 8.180 1.00 24.21 4 CD ILE L 3 32.355 1.270 8.270 1.0025.48 5 C ILE L 3 30.888 -0.418 10.820 1.0021.44 6 0 ILE L 3 29.871 -1.082 10.995 1.0020.56 9 N ILE L 3 32.253 -2.429 10.853 1 .0020.99 I11 CA ILE L 3 32.105 -1.078 10.243 1.00 21.17 12 N VAL L 4 30.990 0.881 11.105 1.00 20.05 14 CA VAL L 4 29.896 1.599 11.741 1.00 20.43 15 GB VAL L 4 30.381 2.218 13.048 1.00 17.54 16 CGl VAL L 4 29.197 2.800 13.811 1.00 19.60 17 CG2 VAL L 4 31.096 1.156 13.881 1.00 17.28 18 C VALL 4 29.326 2.701 10.850 1.00 20.60 19 0 VALL 4 30.054 3.606 10.449 1.0020.97 20 N VAL L 5 28.011 2.621 10.592 1.00 20.30 22 CA VAL L 5 27.3 15 3.571 9.733 1.00 17.97 23 GB3 VAL L 5 26.358 2.798 8.809 1.00 17.56 24 CGI VAL L 5 25.506 3.735 7.957 1.00 16.02 25 CG2 VAL L 5 27.175 1.852 7.930 1.00 17.98 26 C VAL L 5 26.543 4.542 10.611 1.00 18.99 27 0 VALL 5 25.657 4.124 11.342 1.00 18.18 28 N THR L 6 26.884 5.823 10.548 1.00 17.10 30 CA THR L 6 26.268 6.830 11.456 1.00 16.73 31 GB3 THR L 6 27.382 7.654 12.134 1.00 15.12 32 OGI THRL 6 28.147 6.801 12.972 1.00 17.77 34 CG2 THR L 6 26.834 8.782 12.972 1.00 20.38 35 C THRL 6 25.301 7.783 10.753 1.00 15.26 36 0 THR L 6 25.593 8.273 9.658 1.00 14.60 37 N GLN L 7 24.149 8.058 11.416 1.00 14.21 39 CA GLN L 7 23.142 8.992 10.920 1.00 9.76 40 GB3 GLN L 7 21.885 8.241 10.518 1.00 8.55 41 CG GLN L 7 22.057 7.199 9.423 1.00 3.66 42 CD GLN L 7 20.729 6.615 9.060 1.00 4.16 43 OE1 GLN L 7 20.464 5.462 9.328 1.00 10.06 44 NE2 GLN L 7 19.846 7.4 17 8.477 1.00 2.55 47 C GLN L 7 22.792 9.979 12.041 1.00 12.95 48 0 GLN L 7 23.187 9.761 13.186 1.00 12.95 49 N GLUJL 8 22.069 11.059 11.708 1.00 14.59 51 CA GLU L 8 21.637 12.040 12.711 1.00 9.44 52 GB GLU L 8 21.113 13.314 12.073 1.00 3.83 53 CG GLU L 8 22.174 14.132 11.394 1.00 8.12 54 CD GLU L 8 22.252 13.870 9.886 1.00 12.60 55 OEI GLU L 8 21.617 12.890 9.417 1.00 8.76 56 0E2 GLU L 8 22.962 14.647 9.168 1.00 12.58 'C GLU L 8 O GLU L 8 IN SER L 9 CA SER L 9 GB3 SER L 9 OG SER L 9 iC SER L 9 0 SER L 9 N ALAL 10 CA ALA L 10 GB ALA L 10 I C ALA L 10 10 ALA L 10 3 N LEU L 11 5 GA LEU L I11 5 GB LEU L 11 7 CG LEU L 11 3 CD1 LEU L I11 CD2 LEU L I11 C LEUL 11 1 0 LEUL 11 20.521 11.441 1 19.632 10.819 1 20.492 11.676 1.

19.452 11.049 19.753 11.118 20.332 12.351 18.098 11.562 1.

17.176 10.785 1 17.926 12.851 16.586 13.348 15.775 13.505 16.689 14.682 17.644 15.388 15.696 15.040 15.657 16.351 16.162 16.267 17.513 15.589 3.515 1.00 9.97 2.949 1.00 10.41 4.825 1.00 11.56 15.611 1.00 8.58 17.124 1.00 14.23 17.498 1.00 21.30 5.319 1.00 7.24 5.235 1.00 6.90 15.161 1.00 6.82 14.866 1.00 6.68 16.147 1.00 9.20 14.231 1.00 6.99 14.502 1.00 8.81 13.440 1.00 7.46 12.799 1.00 6.63 11.333 1.00 10.52 11.044 1.00 10.17 17.767 15.551 9.544 1.00 8.53 18.631 16.325 11.724 1.00 7.59 14.205 16.806 12.766 1.00 5.60 13.331 15.972 12.663 1.00 7.61 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -163-

ATOM

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82 84 85 86 88 89 90 91 93 94 95 97 98 99 100 102 103 104 106 107 108 109 110

III

112 113 114 115 117 118 119 120 122 123 124 125 1 26 1 27 1 28 1 29 1 30 132 133 1 34 1 36 137 138 141 1 4 143 1 4' 1 41 1 4 1 4 15 15: 1 5 15: 15' 16 16 16 16 16 16 16 16 N THR L 12 GA THR L 12 GB3 TAR L 12 OG I TI-RL 12 CG2 THR L 12 C THR L 12 THR L 12 THR L 13 GA THR L 13 GB3 THR L 13 OG1ITHR L 13 GG2 THR L 13 C THR L 13 0 THR L 13 N SER L 14 GA SER L 14 GB3 SER L 14 OG SER L 14 C SER L 14 O SER L 14 N PRO L 15 GD PRO L 15 GA PRO L 15 GB3 PRO L 15 CG PRO L 15 C PRO L 15 O PRO L 15 N GLY L 16 GA GLY L 16 C GLY L 16 0 GLY L 16 N GLU L 17 CA GLU L 17 CB GLU L 17 CG GLU L 17 CID GLU L 17 0E1 GLU L 17 OE2 GLU L 17 G GLU L 17 O GLU L 17 IN THR L 18 C A THR L 18 GB THR L 18 ~OG1ITHR L 18 GG2 THR L 18 G THR L 18 10 THR L 18 N VAL L 19 C A VAL L 19 GB VAL L 19 CGGIIVAL L 19 ICG2 VAL L 19 C VAL L 19 O VAL L 19 7 N THRL 20 G A THR L 20 G B THR L 20 1 OGI THRL 20 3 GG2 THR L 20 4 C THRL 20 5 0 THR L 20 6 N LEU L21 8 GA LEU L 21 9 GB LEU L 21 0 CG LEU L 21 1 GDI LEU L 21 2 GD2 LEU L 21 3GC LEUL 21 4 0 LEU L21 5 N THR L22 7 GA THR L 22 8 GB THR L 22 13.961 18.126 12.816 1.00 4.15 12.600 18.697 12.814 1.00 6.68 12.357 19.494 14.139 1.00 10.20 12.556 18.628 15.276 1.00 10.18 10.955 20.089 14.157 1.00 4.50 12.442 19.705 11.661 1.00 9.42 13.343 20.532 11.404 1.00 11.76 11.321 19.713 11.016 1.00 12.34 11.160 20.652 9.956 1.00 13.42 11.709 20.016 8.626 1.00 15.26 12.053 21.031 7.672 1.00 19.73 10.695 19.089 8.020 1.00 15.31 9.703 21.053 9.814 1.00 13.88 8.766 20.263 10.13 1 1.00 12.15 9.474 22.296 9.389 1.00 8.75 8.119 22.684 9.120 1.00 10.75 7.964 24.220 9.106 1.00 15.90 8.794 24.839 10.126 1.00 21.10 7.802 22.124 7.784 1.00 10.99 8.703 21.910 6.981 1.00 10.06 6.560 21.807 7.514 1.00 11.57 5.417 21.894 8.417 1.00 11.51 6.211 21.264 6.210 1.00 13.73 4.712 20.965 6.322 1.00 12.67 4.257 21.8 10 7.463 1.00 13.25 6.562 22.287 5.106 1.00 15.44 6.620 23.482 5.388 1.00 14.98 6.849 21.806 3.887 1.00 12.73 7.184 22.686 2.796 1.00 11.86 8.645 23.047 2.740 1.00 11.99 9.097 23.650 1.786 1.00 16.69 9.405 22.729 3.739 1.00 10.28 10.801 23.014 3.660 1.00 8.33 11.319 23.510 5.002 1.00 6.44 10.648 24.808 5.438 1.00 11.47 10.766 25.875 4.353 1.00 5.30 11.949 26.218 3.967 1.00 6.09 9.681 26.343 3.900 1.00 7.10 11.553 21.772 3.219 1.00 8.34 10.995 20.665 3.241 1.00 10.48 12.821 21.961 2.861 1.00 7.25 13.682 20.866 2.407 1.00 6.74 14.576 21.383 1.236 1.00 3.14 13.718 21.634 0.084 1.00 2.24 15.708 20.418 0.909 1.00 5.50 14.587 20.422 3.544 1.00 5.28 15.129 21.265 4.271 1.00 4.15 14.815 19.121 3.646 1.00 5.05 15.711 18.587 4.662 1.00 6.85 14.934 17.754 5.770 1.00 8.11 14.554 18.573 6.983 1.00 12.22 13.670 17.120 5.170 1.00 11.25 16.695 17.609 4.010 1.00 7.00 16.323 16.856 3.123 1.00 8.38 17.897 17.588 4.511 1.00 7.91 18.861 16.618 4.098 1.00 10.04 20.046 17.270 3.319 1.00 8.38 19.553 17.736 2.053 1.00 10.18 21.188 16.287 3.104 1.00 7.29 19.379 15.843 5.324 1.00 10.78 19.752 16.441 6.354 1.00 14.77 19.313 14.510 5.201 1.00 8.97 19.829 13.570 6.174 1.00 5.71 18.819 12.417 6.324 1.00 7.30 17.448 12.710 6.922 1.00 3.52 16.618 13.549 5.972 1.00 12.30 16.726 11.431 7.221 1.00 5.61 21.108 13.008 5.612 1.00 5.00 21.155 12.736 4.403 1.00 6.66 22.151 12.817 6.426 1.00 4.47 23.366 12.204 5.920 1.00 8.68 24.593 13.096 6.059 1.00 8.60 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -164-

ATOM

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169 171 172 173 174 176 177 178 179 180 181 183 184 185 186 187 189 190 193 196 197 198 200 201 202 204 205 206 208 209 210 212 213 214 216 217 218 220 221 222 223 225 226 227 228 230 231 232 233 234 236 237 238 239 240 241 242 244 245 246 248 249 250 251 253 254 255 257 258 259 260 262 OG I TH-RL 22 CG2 THR L 22 C THR L22 O THR L22 N CYS L23 CA CYS L 23 GB CYS L 23 SG CYS L 23 C CYS L23 O CYS L23 N ARG L24 CA ARG L 24 CB ARG L 24 CG ARG L 24 CD ARG L 24 NE ARG L 24 CZ ARG L 24 NHI ARG L 24 NH2 ARG L 24 C ARG L24 0 ARG L24 N SER L25 CA SER L 25 GB SER L 25 OG SER L 25 C SER L25 O SER L25 N SER L26 CA SER L 26 CB SER L 26 OG SER L 26 C SER L26 O SER L26 N THR L27 CA THR L 27 CB THR L 27 OGI THRL 27 CG2 THR L 27 C THR L27 0 THR L 27 N GLY L27A CA GLY L 27! C GLY L27A 24.910 13.292 7.446 1.00 13.20 24.362 14.415 5.379 1.00 12.92 23.674 10.813 6.543 1.00 12.45 23.079 10.380 7.573 1.00 12.78 24.608 10.148 5.934 1.00 9.70 24.952 8.812 6.3 15 1.00 12.79 24.114 7.891 5.444 1.00 11.70 24.573 6.172 5.437 1.00 14.38 26.425 8.616 6.085 1.00 11.83 26.880 8.699 4.961 1.00 13.63 27.201 8.397 7.146 1.00 13.74 28.638 8.236 6.965 1.00 15.34 29.442 9.275 7.741 1.00 17.58 29.171 9.346 9.214 1.0023.61 30.177 10.263 9.890 1.00 27.66 31.558 9.839 9.613 1.00 30.74 32.508 10.677 9.195 0.01 28.45 33.729 10.222 8.952 0.01 28.77 32.247 11.970 9.031 0.01 27.96 29.123 6.869 7.327 1.00 16.36 28.461 6.146 8.081 1.00 15.58 30.274 6.517 6.760 1.00 14.90 30.900 5.237 7.014 1.00 15.33 31.273 4.582 5.683 1.00 20.16 32.252 3.571 5.852 1.00 23.32 32.145 5.470 7.869 1.00 14.75 32.859 6.422 7.653 1.00 16.11 32.381 4.626 8.851 1.00 15.20 33.555 4.767 9.720 1.00 19.00 33.38 1 3.884 10.959 1.00 16.96 33.196 2.519 10.578 1.00 19.34 34.858 4.349 9.001 1.00 19.93 35.936 4.445 9.570 1.00 23.14 34.768 3.853 7.78 1 1.00 20.53 35.958 3.362 7.120 1.00 19.87 35.651 2.067 6.419 1.00 21.22 34.472 2.209 5.633 1.00 24.06 35.417 0.987 7.453 1.00 23.05 36.536 4.375 6.153 1.00 19.65 37.728 4.343 5.822 1.00 20.98 35.697 5.293 5.715 1.0020.47 36.148 6.333 4.827 1.00 15.37 34.981 6.909 4.102 1.00 14.56 33.871 6.786 4.564 1.00 16.44 35.237 7.538 2.959 1.00 14.44 34.183 8.158 2.158 1.00 13.84 34.801 8.852 0.922 1.00 10.44 33.157 7.151 1.678 1.00 14.20 33.507 6.028 1.294 1.00 16.84 3 1.915 7.550 1.682 1.00 12.61 30.894 6.755 1.040 1.00 14.17 29.533 7.077 1.632 1.00 13.42 GLY L 27A ALA L 27B LALA L 27E I ALA L 27E ALA L 27B ALA L 27B VAL L 27C VAL L 27C IVAL L 27( CGI VAL L 27C 28.465 6.232 0.979 1.00 14.92 CG2 VAL L 27C 29.592 6.828 3.130 1.00 14.29 C VAL L 27C 30.903 7.081 -0.471 1.00 16.22 O VAL L 27C 30.837 8.264 -0.849 1.00 16.42 N THR L 28 3 1.047 6.039 -1.322 1.00 15.73 CA THR L 28 3 1.068 6.215 -2.805 1.00 14.38 CB THR L 28 32.386 5.725 -3.453 1.00 12.94 OGI THRL 28 32.412 4.313 -3.470 1.00 13.65 CG2 THR L 28 33.597 6.211 -2.699 1.00 11.90 C THR L 28 29.924 5.439 -3.450 1.00 12.92 O THR L 28 29.103 4.824 -2.764 1.00 9.64 N THR L 29 29.850 5.474 -4.765 1.00 12.65 CA THR L 29 28.780 4.786 -5.461 1.00 14.40 GB THR L 29 28.797 5.088 -6.978 1.00 15.28 OGI THR L 29 30.146 4.883 -7.468 1.00 16.73 CG2 THR L 29 28.337 6.524 -7.253 1.00 16.74 C THR L 29 28.904 3.287 -5.275 1.00 14.04 O THR L 29 27.939 2.555 -5.436 1.00 17.19 N SER L 30 30.085 2.840 -4.924 1.00 14.83 CA SER L 30 30.306 1.429 -4.697 1.00 16.69 SUBSTITiUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -165-

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263 264 266 267 268 270 271 272 273 274 277 278 279 281 282 283 284 285 286 287 288 289 291 292 293 295 296 297 298 299 301 302 303 304 305 308 309 310 312 313 314 315 316 317 318 319 321 322 323 324 325 326 328 329 330 331 332 333 334 336 337 338 339 340 341 344 345 346 348 349 350 351

I

*1 -B SER L 30 )G SER L 30 SER L 30 )SER L 30 ,J ASN L31 A ASN L 31 -B ASN L 31 "G ASN L 31 IASN L 31 qD2 ASN L 31 -ASNL 31 D ASN L31 q TYR L32 :A TYR L 32 B1 TYR L 32 G TYR L 32 ZD1ITYR L 32 2131TYR L 32 D2 TYR L 32 E2 TYR L 32 Z TYR L 32 DH TYR L 32 i TYR L32 0 TYR L 32 Nl ALA L33 CA ALA L 33 CB ALA L 33 C ALA L 33 0' ALA L33 N ASN L34 CA ASN L 34 CB ASN L 34 CG ASN L 34 ODI ASN L 34 ND2 ASN L 34 C ASN L34 0 ASN L34 N TRP L35 CA TRP L 35 GB TRP L 35 CG TRP L 35 CD2 TRP L 35 CE2 TRP L 35 CE3 TRP L 35 CDI TRP L 35 NEI TRP L 35 CZ2 TRP L 35 CZ3 TRP L 35 CH2 TRP L 35 C TRP L35 0 TRPL 35 N VAL L 36 CA VAL L 36 CB VAL L 36 CG1 VAL L 36 CG2 VAL L 36 C VAL L36 O VAL L 36 N GLN L37 CA GLN L 37 CB GLN L 37 CG GLN L 37 CD GLN L 37 OE1 GLN L 37 NE2 GLN L 37 C GLN L37 O GLN L37 N GLU L38 CA GLU L 38 GB GLU L 38 PCG GLU L 38 CD GLU L 38 3 1.790 1.168 -4.607 1.00 18.52 32.399 1.455 -5.845 1.00 22.73 29.628 0.939 -3.418 1.00 18.22 29.565 -0.247 -3.177 1.00 17.69 29.154 1.843 -2.585 1.00 16.05 28.467 1.432 -1.358 1.00 12.29 28.710 2.456 -0.265 1.00 9.73 30.118 2.424 0.219 1.00 5.99 30.833 3.398 0.117 1.00 9.76 30.548 1.320 0.741 1.00 3.79 26.988 1.277 -1.585 1.00 10.21 26.242 0.937 -0.663 1.00 9.59 26.575 1.527 -2.829 1.00 8.64 25.176 1.475 -3.211 1.00 7.71 24.830 0.081 -3.773 1.00 11.29 25.721 -0.367 -4.925 1.00 11.41 27.019 -0.834 -4.681 1.00 14.39 27.869 -1.196 -5.711 1.00 14.44 25.296 -0.298 -6.259' 1.00 17T67 26.145 -0.666 -7.326 1.00 11.36 27.437 1. 108 -7.043 1.00 17.13 28.334 -1.419 -8.085 1.0021.48 24.228 1.852 -2.055 1.00 11.23 23.288 1.105 -1.733 1.00 6.50 24.445 3.043 -1.455 1.00 11.42 23.624 3.480 -0.308 1.00 11.19 23.921 4.926 0.065 1.00 10.80 22.133 3.371 -0.547 1.00 10.34 21.660 3.893 -1.543 1.00 8.45 21.401 2.715 0.396 1.00 7.12 19.925 2.664 0.367 1.00 5.84 19.388 1.251 0.564 1.00 3.46 19.488 0.414 -0.691 1.00 7.07 18.487 -0.063 -1.223 1.00 5.20 20.700 0.240 -1.163 1.00 5.40 19.318 3.528 1.458 1.00 5.10 19.964 3.789 2.435 1.00 6.58 18.076 3.957 1.259 1.00 5.01 17.339 4.694 2.278 1.00 6.70 17.175 6.215 1.933 1.00 7.73 18.477 6.997 1.932 1.00 7.11 19.075 7.641 3.080 1.00 8.09 20.330 8.111 2.697 1.00 5.38 18.654 7.858 4.418 1.00 10.50 19.373 7.125 0.894 1.00 4.99 20.472 7.780 1.351 1.00 6.98 21.206 8.791 3.595 1.00 5.76 19.526 8.534 5.295 1.00 6.19 20.785 8.990 4.879 1.00 3.95 16.000 4.036 2.4 14 1.00 6.29 15.314 3.796 1.403 1.00 6.53 15.674 3.704 3.665 1.00 5.99 14.479 2.971 4.045 1.00 5.23 14.826 1.555 4.651 1.00 6.23 13.540 0.839 5.092 1.00 2.37 15.571 0.693 3.605 1.00 3.99 13.692 3.769 5.086 1.00 4.86 14.255 4.313 6.025 1.00 7.07 12.395 3.803 4.906 1.00 5.26 11.5 12 4.532 5.786 1.00 10.98 10.505 5.305 4.967 1.00 10.61 9.720 6.295 5.788 1.00 10.14 8.601 6.850 4.987 1.00 15.44 7.787 6.096 4.465 1.00 18.50 8.553 8.166 4.858 1.00 15.77 10.723 3.613 6.694 1.00 11.84 10.134 2.657 6.222 1.00 15.29 10.689 3.945 7.989 1.00 13.42 9.861 3.213 8.930 1.00 12.58 10.678 2.719 10.133 1.00 12.59 9.830 1.991 11.202 1.00 11.75 10.622 1.505 12.384 1.00 9.26 SUBSTITIUTI SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -166-

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352 353 354 355 356 358 359 360 361 362 363 367 368 369 370 371 372 373 374 375 376 378 379 380 381 382 384 385 386 387 388 390 391 393 394 395 397 398 399 400 401 402 403 404 406 407 408 409 410 411 412 413 414 415 416 418 419 420 422 423 424 425 427 428 42S 43( 4 3, 43' 43' 43 43' 43.

OEI GLU L 38 OE2 GLU L 38 C GLU L38 0 GLU L38 N LYS L39 CA LYS L 39 GB LYS L 39 CG LYS L 39 CD LYS L 39 CE LYS L 39 NZ LYS L 39 C LYS L39 O LYS L39 N PRO L40 CD PRO L 40 CA PRO L 40 GB PRO L 40 CG PRO L 40 C PROL 40 O PRO L40 N ALA L41 CA ALA L 41 GB ALA L 41 C ALAL 41 O ALAL 41 N HSL 42 CA HIS L 42 GB HIS L 42 CG HIS L 42 GD2 HIS L 42 NDI HIS L 42 GEl HIS L 42 NE2 HIS L 42 G HIS L42 0 HIS L42 N LEU L43 GA LEU L 43 GB LEU L 43 CG LEU L 43 CD I LEU L 43 CD2 LEU L 43 C LEU L43 O LEU L43 N PHE L44 CA-PHE L 44 GB PHE L 44 CG PHE L 44 CDI PHE L 44 CD2 PHE L 44 CElI PHE L 44 CE2 PHE L 44 CZ PHE L 44 C PHE L44 0 PHE L44 N THR L45 GA THR L 45 GB THR L 45 OGI THRL 45 CG2 THR L 45 C THR L 45 0O THR L45 N GLY L46 GA GLY L 46 ~C GLY L46 0O GLY L46 )N LEU L47 CA LEU L 47 C B LEU L 47 ICG LEU L 47 5CD I LEU L 47 5CD2 LEU L 47 7 C LEU L47 11.751 1.915 12.540 1.00 12.30 10. 103 0.690 13.161 1.00 17.41 8.719 4.098 9.460 1.00 14.00 8.964 5.098 10.173 1.00 12.02 7.488 3.747 9.117 1.00 13.36 6.363 4.431 9.687 1.00 15.90 5.353 4.768 8.628 1.00 14.39 5.795 5.954 7.803 1.00 15.78 4.651 6.478 6.961 1.00 22.14 5.167 7.451 5.905 1.00 25.73 4.106 7.921 4.959 1.00 27.82 5.723 3.624 10.838 1.00 20.86 5.775 2.359 10.890 1.00 18.39 5.128 4.335 11.810 1.0025.47 4.973 5.792 11.884 1.00 28.62 4.486 3.717 12.952 1.00 28.32 3.528 4.812 13.494 1.00 28.73 3.578 5.887 12.458 1.00 30.27 3.779 2.403 12.593 1.00 28.70 2.898 2.34 1 11.688 1.00 25.53 4.276 1.365 13.295 1.00 30.46 3.803 -0.018 13.225 1.00 28.13 2.411 129 12.599 1.00 29.92 4.789 -0.885 12.485 1.00 24.45 4.403 -1.889 11.908 1.00 26.51 6.069 -0.511 12.499 1.0022.07 7.079 -1.337 11.853 1.00 20.06 7.082 -2.734 12.472 1.00 20.43 7.624 -2.730 13.832 1.00 17.71 7.030 -2.688 15.058 1.00 17.56 8.958 -2.573 14.058 1.00 21.55 9.230 -2.422 15.333 1.00 19.46 8.081 -2.487 15.944 1.00 17.49 6.815 -1.469 10.375 1.00 21.88 7.010 -2.542 9.809 1.00 22.22 6.335 -0.40 1 9.749 1.00 20.03 6.067 -0.450 8.339 1.00 20.01 4.849 0.389 8.019 1.00 24.58 3.599 0.015 8.814 1.00 27.32 2.559 1.122 8.684 1.00 26.38 3.071 -1.374 8.380 1.00 24.37 7.271 0.088 7.621 1.00 18.27 7.582 1.270 7.742 1.00 18.64 7.977 -0.790 6.930 1.00 17.14 9.188 -0.404 6.239 1.00 13.89 10.276 -1.395 6.558 1.00 10.76 10.863 -1.268 7.932 1.00 8.20 10.285 -1.925 9.005 1.00 10.99 12.017 -0.526 8.135 1.00 13.17 10.834 -1.852 10.273 1.00 11.48 12.588 -0.445 9.399 1.00 12.05 11.987 -1.110 10.476 1.00 12.67 8.981 -0.332 4.726 1.00 14.13 8.262 -1.129 4.142 1.00 14.69 9.634 0.619 4.092 1.00 14.63 9.508 0.771 2.678 1.00 12.14 8.295 1.652 2.352 1.00 14.73 8.083 1.684 0.944 1.00 25.05 8.519 3.065 2.828 1.00 19.97 10.773 1.398 2.181 1.00 11.69 11.316 2.253 2.826 1.00 9.53 11.293 0.878 1.083 1.00 11.34 12.521 1.398 0.526 1.00 7.20 12.252 2.593 -0.33 1 1.00 7.78 11.283 2.595 -1.140 1.00 10.42 13.092 3.602 -0.166 1.00 7.54 12.929 4.861 -0.890 1.00 7.47 13.071 6.050 0.080 1.00 6.90 12.253 5.969 1.362 1.00 6.26 12.782 6.944 2.383 1.00 11.14 10.785 6.173 1.052 1.00 2.41 13.968 4.989 -2.015 1.00 5.84 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCTIG B98/02542 -167-

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438 0 LEU L47 439 N ILE L 48 441 CA ILE L 48 442 GB ILE L 48 443 CG2 ILE L 48 444 CGI ILE L 48 445 CD ILE L 48 446 C ILE L48 447 0 ILE L 48 448 N GLY L49 450 CA GLY L 49 451 C GLY L 49 452 0 GLY L49 453 N GLYL 50 455 CA GLY L 50 456 C GLYL 50 457 0 GLYL 50 458 N THR L51 460 GA THR L 51 461 GB THR L 51 462 OG ITHR L 51 464 CG2 THR L 51 465 C THR L 51 466 0 THR L 51 467 N ASNL 52 469 GA ASN L 52 470 GB ASN L 52 471 CG ASN L 52 472 ODI ASN L 52 473 ND2 ASN L 52 476 C ASN L 52 477 0 ASNL 52 478 N ASNL 53 480 CA ASN L 53 481 GB ASN L 53 482 CG ASN L 53 483 ODI ASN L 53 484 ND2 ASN L 53 487 C ASNLS53 488 0 ASN L 53 489 N ARGL 54 491 GA ARG L 54 492 GB ARG L 54 493 CG ARG L 54 494 GD ARG L 54 495 NE ARG L 54 497 CZ ARG L 54 498 NH1I ARG L 5' 501 NH2 ARG L 5' 504GC ARGLS54 505 0 ARGL 54 506 N ALAL 55 508 GA ALA L 55 509 GB ALA L 55 510OG ALAL 55 511 0 ALA L 55 512 N PRO L56 513 CD PRO L 56 514 GA PRO L 56 515 GB PRO L 56 516 CG PRO L 56 517 C PRO L 56 518 0 PRO L 56 519 N GLYL 57 521 GA GLY L 5, 522GC GLY L57 523 0 GLYL 57 524 N VAL L58 526 GA VAL L 51 527 GB VAL L 51 528 CGI VAL L 5 529 CG2 VAL L 5 13.597 5.286 -3.141 1.00 8.92 15.239 4.746 -1.673 1.00 9.03 16.377 4.909 -2.566 1.00 7.03 17.287 6.078 -2.094 1.00 7.21 18.552 6.176 -2.934 1.00 9.51 16.524 7.405 -2.047 1.00 8.82 16.013 7.933 -3.364 1.00 7.80 17.245 3.644 -2.530 1.00 8.61 17.458 3.068 -1.462 1.00 10.60 17.755 3.237 -3.704 1.00 7.04 18.697 2.142 -3.805 1.00 2.00 19.833 2.550 -4.716 1.00 7.57 19.716 3.479 -5.538 1.00 14.41 20.941 1.930 -4.590 1.00 9.91 22.036 2.293 -5.431 1.00 9.21 22.299 3.789 -5.458 1.00 12.31 22.341 4.370 -6.518 1.00 12.48 22.465 4.390 -4.284 1.00 10.33 22.795 5.834 -4.116 1.00 12.06 24.092 6.281 -4.869 1.00 11.87 25.226 5.464 -4.501 1.00 7.57 24.409 7.726 -4.5 14 1.00 11.63 21.672 6.817 -4.460 1.00 11.67 21.343 7.660 -3.638 1.00 11.93 21.046 6.703 -5.637 1.00 12.21 20.092 7.718 -6.054 1.00 13.73 20.824 8.824 -6.808 1.00 18.43 21.621 8.271 -7.967 1.00 24.37 21.164 7.364 -8.639 1.00 22.65 22.842 8.774 -8.182 1.00 28.21 18.964 7.205 -6.914 1.00 15.37 18.318 7.975 -7.594 1.00 13.37 18.730 5.916 -6.901 1.00 16.28 17.652 5.350 -7.676 1.00 17.34 18.079 3.979 -8.239 1.00 24.00 17.187 3.406 -9.349 1.00 27.36 17.659 2.594-10.168 1.0033.10 15.91 1 3.799 -9.410 1.00 31.42 16.415 5.210 -6.781 1.00 17.91 16.352 4.394 -5.893 1.00 18.29 15.447 6.010 -7.022 1.00 15.93 14.283 5.977 -6.241 1.00 18.87 13.500 7.233 -6.541 1.00 22.33 12.109 7.273 -5.975 1.00 25.55 11.778 8.681 -5.615 1.0029.54 12.126 9.582 -6.671 1.00 27.82 11.288 9.890 -7.630 1.00 32.19 4 11.669 10.739 -8.561 1.00 35.27 4 10.071 9.344 -7.673 1.00 31.58 13.483 4.725 -6.552 1.00 21.41 13.273 4.403 -7.738 1.00 21.21 13.061 4.010 -5.489 1.00 20.79 12.237 2.803 -5.629 1.00 21.50 12.004 2.154 -4.262 1.00 18.92 10.932 3.185 -6.282 1.00 22.01 10.488 4.307 -6.147 1.00 23.44 10.264 2.268 -6.972 1.00 25.55 10.602 0.823 -7.094 1.00 26.77 9.019 2.583 -7.664 1.00 24.82 8.690 1.270 -8.406 1.00 27.53 9.286 0.224 -7.522 1.00 27.71 7.914 3.046 -6.720 1.00 25.91 7.749 2.531 -5.608 1.00 26.27 7.148 4.025 -7.182 1.00 26.28 6.054 4.562 -6.382 1.00 22.74 6.486 5.620 -5.373 1.00 20.96 5.666 6.38 1 -4.908 1.00 23.79 7.764 5.662 -5.014 1.00 20.25 8 8.231 6.660 -4.079 1.00 18.53 9.680 6.382 -3.699 1.00 15.29 8 10.238 7.551 -2.940 1.00 11.07 8 9.750 5.103 -2.874 1.00 12.65 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -168-

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530 C VAL L58 531 0 VAL L 58 532 N PRO L 59 533 CD PRO L 59 534 CA PRO L 59 535 CB3 PRO L 59 536 CG PRO L 59 537 C PRO L 59 538 0 PROL 59 539 N ALAL 60 541 CA ALA L 60 542 CB ALA L 60 543 C ALAL 60 544 0 ALAL 60 545 N ARGL 61 547 CA ARG L 61 548 GB ARG L 61 549 CG ARG L 61 550 CD ARG L 61 551 NE ARG L 61 553 CZ ARG L 61 554 NH I ARG L 61 557 N-2 ARG L 61 560 C ARG L61 561 0 ARG L 61 562 N PHE L62 564 CA PHE L 62 565 GB3 PHE L 62 566 CG PHE L 62 567 CD I PHE L 62 568 CD2 PHE L 62 569 GEl PHE L 62 570 CE2 PHE L 62 571 CZ PHE L 62 572 C PHE L62 573 0 PHE L 62 574 N SER L 63 576 CA SER L 63 577 GB3 SER L 63 578 OG SER L 63 580 C SER L 63 581 0 SER L 63 582 N GLY L64 584 CA GLY L 64 585 C GLY L64 586 0 GLY L64 587 N SER L 65 589 CA SER L 65 590 GB SER L 65 591 OG SER L 65 593 C SER L 65 594 0 SER L 65 595 N LEU L66 597 CA LEU L 66 598 GB3 LEU L 66 599 CG LEU L 66 600 CD I LEU L 66 601 CD2 LEU L 66 602 C LEU L66 603 0 LEU L66 604 N ILE L 67 606 GA ILE L 67 607 C13 ILE L 67 608 CG2 ILE L 67 609 CG1I ILE L 67 610 GD ILE L 67 611 C ILE L 67 612 0 ILE L 67 613 N GLY L68 615 CA GLY L 68 616 C GLY L68 617 0 GLY L68 8.119 8.077 -4.675 1.00 22.04 8.583 8.324 -5.803 1.00 22.18 7.524 9.045 -3.894 1.00 21.50 6.983 8.863 -2.521 1.00 20.50 7.336 10.449 -4.315 1.00 17.94 6.841 11.133 -3.057 1.00 18.92 6.054 10.043 -2.414 1.00 18.97 8.583 11.092 -4.837 1.00 16.82 9.706 10.918 -4.311 1.00 15.46 8.370 11.873 -5.854 1.00 13.05 9.447 12.523 -6.521 1.00 14.83 8.871 13.289 -7.696 1.00 14.69 10.233 13.424 -5.570 1.00 13.44 11.407 13.633 -5.776 1.00 12.14 9.593 13.928 -4.489 1.00 15.30 10.309 14.825 -3.522 1.00 12.59 9.349 15.408 -2.470 1.00 11.72 8.620 14.397 -1.586 1.00 14.79 7.890 15.077 -0.419 1.00 14.00 7.226 14.114 0.476 1.00 10.99 6.131 13.465 0.114 1.00 11.79 5.556 12.582 0.908 1.00 10.75 5.624 13.684 -1.059 1.00 9.70 11.500 14.173 -2.811 1.00 12.82 12.291 14.876 -2.112 1.00 14.41 11.649 12.845 -2.959 1.00 11.27 12.749 12.133 -2.305 1.00 10.94 12.274 10.739 -1.775 1.00 9.35 11.263 10.787 -0.649 1.00 9.62 11.683 10.906 0.690 1.00 5.49 9.897 10.704 -0.919 1.00 6.68 10.760 10.943 1.698 1.00 2.51 8.968 10.742 0.110 1.00 7.73 9.399 10.864 1.419 1.00 4.66 13.914 11.938 -3.265 1.00 9.16 13.692 11.429 -4.340 1.00 8.82 15.160 12.325 -2.864 1.00 4.85 16.307 12.112 -3.733 1.00 8.59 16.671 13.353 -4.534 1.00 7.17 17.269 14.3 19 -3.694 1.00 12.90 17.511 11.689 -2.946 1.00 7.30 17.703 12.187 -1.852 1.00 9.45 18.286 10.728 -3.503 1.00 5.56 19.495 10.269 -2.889 1.00 4.07 20.676 10.881 -3.568 1.00 9.49 20.620 11.246 -4.766 1.00 12.20 21.758 11.031 -2.872 1.00 6.73 22.865 11.665 -3.485 1.00 9.75 22.581 13.171 -3.683 1.00 8.17 22.791 13.906 -2.475 1.00 10.45 24.064 11.437 -2.652 1.00 10.16 23.978 10.692 -1.662 1.00 10.96 25.182 12.009 -3.085 1.00 10.68 26.453 11.877 -2.394 1.00 9.69 27.441 11.114 -3.317 1.00 13.61 28.218 9.861 -2.820 1.00 9.87 27.385 8.987 -1.932 1.00 8.09 28.680 9.048 -4.022 1.00 8.69 26.918 13.316 -2.147 1.00 12.92 27.054 14.087 -3.082 1.00 10.87 27.091 13.694 -0.865 1.00 12.45 27.534 15.048 -0.518 1.00 11.66 26.437 15.786 0.334 1.00 12.96 26.820 17.222 0.568 1.00 13.30 25.074 15.750 -0.357 1.00 13.53 23.962 16.437 0.419 1.00 11.05 28.837 14.913 0.268 1.00 12.31 28.856 14.332 1.339 1.00 13.03 29.946 15.384 -0.274 1.00 13.08 31.199 15.196 0.416 1.00 12.32 3 1.463 13.701 0.568 1.00 17.92 3 1.201 12.934 -0.393 1.00 16.67 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -169-

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618 N ASP L 69 620 CA ASP L 69 621 GB ASP L 69 622 CG ASP L 69 623 OD I ASP L 69 624 0D2 ASP L 69 625 C ASP L 69 626 0 ASP L69 627 N LYS L 70 629 CA LYS L 70 630 GB LYS L 70 631 CG LYS L 70 632 CD LYS L 70 633 CE LYS L 70 634 NZ LYS L 70 638 C LYS L 70 639 0 LYS L 70 640 N ALAL 71 642 CA ALA L 71 643 GB ALA L 71 644 C ALA L71 645 0 ALA L 71 646 N ALA L 72 648 CA ALA L 72 649 GB ALA L 72 650 C ALA L72 651 0 ALA L 72 652 N LEU L73 654 CA LEU L 73 655 GB LEU L 73 656 CG LEU L 73 657 CDI LEUL 73 658 CD2 LEU L 73 659 C LEU L 73 660 0 LEU L 73 661 N THR L 74 663 CA THR L 74 664 CB THR L 74 665 OGI THRL 74 667 CG2 THR L 74 668 C THR L 74 669 0 THR L 74 670 N ILE L 75 672 CA ILE L 75 673 GB ILE L 75 674 CG2 ILE L 75 675 CG I ILE L 75 676 CD ILE L 75 677 C ILE L 75 678 0 ILE L 75 679 N THR L 76 681 CA THR L 76 682 CB THR L 76 683 OG1 THR L 76 685 CG2 THR L 76 686 C TI-R L 76 687 0 THR L 76 688 N GLY L77 690 CA GLY L 77 691 C GLY L 77 692 0 GLY L77 693 N ALA L78 695 CA ALA L 78 696 CB ALA L 78 697 C ALA L78 698 0 ALA L78 699 N GLN L79 701 CA GLN L 79 702 GB GLN L 79 703 CG GLN L 79 704 CD GLN L 79 705 OEI GLN L 79 3 1.962 13.259 1.747 1.00 16.48 32.244 11.827 1.941 1.00 18.10 33.350 11.576 2.960 1.00 24.05 34.617 12.363 2.730 1.00 31.27 35.202 12.302 1.597 1.00 32.40 35.038 13.053 3.707 1.00 39.08 31.040 11.041 2.429 1.00 14.56 3 1.213 9.925 2.886 1.00 16.00 29.837 11.573 2.321 1.00 11.13 28.693 10.853 2.847 1.00 11.46 28.125 11.600 4.028 1.00 11.39 29.0 12 11.550 5.248 1.00 18.50 28.263 12.078 6.455 1.0020.15 28.152 13.574 6.391 1.0022.74 29.502 14.187 6.360 1.0027.69 27.593 10.635 1.869 1.00 10.75 27.478 11.366 0.879 1.00 11.35 26.759 9.619 2.144 1.00 6.32 25.537 9.475 1.385 1.00 2.44 25.056 8.033 1.399 1.00 2.00 24.483 10.396 2.027 1.00 6.77 24.518 10.670 3.253 1.00 6.10 23.557 10.888 1.235 1.00 5.00 22.570 11.814 1.741 1.00 6.21 23.042 13.257 1.524 1.00 3.82 21.215 11.570 1.100 1.00 4.44 21.109 11.043 -0.045 1.00 6.60 20.186 11.854 1.883 1.00 5.08 18.799 11.765 1.446 1.00 4.01 17.970 10.823 2.3 19 1.00 4.42 16.494 10.793 1.959 1.00 4.74 16.290 9.999 0.667 1.00 4.42 15.684 10.194 3.100 1.00 8.67 18.198 13.141 1.576 1.00 5.38 18.297 13.756 2.622 1.00 9.62 17.617 13.635 0.531 1.00 7.72 17.024 14.935 0.566 1.00 6.80 17.721 15.910 -0.447 1.00 9.87 19.099 16.158 -0.011 1.00 4.69 16.961 17.216 -0.538 1.00 4.65 15.593 14.857 0.275 1.00 7.31 15.182 14.221 -0.672 1.00 6.60 14.816 15.472 1.136 1.00 8.15 13.413 15.560 0.923 1.00 9.10 12.620 15.131 2.171 1.00 11.95 11.148 15.053 1.822 1.00 12.49 13.146 13.794 2.729 1.00 16.99 12.335 13.263 3.909 1.00 15.52 13.092 17.018 0.628 1.00 12.05 13.192 17.866 1.520 1.00 10.42 12.722 17.309 -0.627 1.00 13.27 12.393 18.674 -1.039 1.00 11.86 12.724 18.884 -2.519 1.00 8.49 14.092 18.564 -2.749 1.00 7.34 12.480 20.309 -2.892 1.00 8.93 10.907 18.987 -0.848 1.00 15.75 10.051 18.407 -1.523 1.00 19.95 10.593 19.939 0.038 1.00 17.30 9.197 20.267 0.278 1.00 15.95 8.573 19.198 1.109 1.00 16.40 7.498 18.704 0.788 1.00 17.47 9.247 18.836 2.189 1.00 16.13 8.771 17.740 3.065 1.00 16.88 9.672 17.614 4.284 1.00 15.72 7.304 17.900 3.476 1.00 17.09 6.803 19.006 3.676 1.00 20.02 6.596 16.779 3.543 1.00 16.23 5.203 16.781 3.933 1.00 14.31 4.426 16.047 2.865 1.00 13.55 4.481 16.789 1.539 1.00 17.28 3.673 16.137 0.434 1.00 22.72 3.812 16.511 -0.749 1.00 28.20 SUBSTITUT SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/G B98/02 542 -170-

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706 709 710 711 713 714 715 717 718 719 720 722 723 724 725 726 727 728 729 730 732 733 734 735 736 737 738 739 741 742 743 744 745 746 747 748 749 751 752 753 754 755 757 758 759 760 761 762 763 764 766 767 768 769 770 771 772 773 774 776 777 778 780 781 782 783 784 785 78( 78'2 781 78~ NE2 GLN L 79 C GLN L79 O GLN L79 N THR L80 CA THR L 80 GB THR L 80 OG ITHR L 80 CG2 THR L 80 C THR L 80 O THR L 80 N GLUL 81 GA GLU L 81 GB GLU L 81 CG GLU L 81 GD GLU L 81 OE1 GLU L 81 OE2 GLU L 81 C GLU L81 O GLU L81 N ASP L 82 GA ASP L 82 GB3 ASP L 82 CG ASPL, 82 ODI ASP L 82 0D2 ASP L 82 C ASP L82 ASP L82 N GLU L83 CA GLU L 83 GB GLU L 83 CG GLU L 83 GD GLU L 83 OEI GLU L 83 OE2 GLU L 83 C GLU L83 O GLU L 83 N ALA L84 GA ALA L 84 GB ALA L 84 C ALA L 84 0 ALA L 84 N ILE L 85 GA ILE L 85 GB ILE L 85 GG2 ILE L 85 CG I ILE L 85 CD ILE L 85 C ILE L85 O ILE L85 N TYR L 86 GA TYR L 86 GB TYR L 86 CG TYR L 86 CD ITYR L 86 GEl TYR L 86 GD2TYRL 86 GE2 TYR L 86 CZ TYR L 86 OH TYR L 86 G TYR L 86 O TYR L 86 N PHEL 87 GA PHE L 87 GB3 PHE L 87 CG PHE L 87 CD1I PHE L 87 ICD2 PHE L 87 GEl PHE L 87 CE2 PHE L 87 C Z PHE L 87 IGC PHE L87 o PHEL 87 2.814 15.173 0.777 1.00 22.58 4.997 16.154 5.332 1.00 14.89 5.885 15.484 5.845 1.00 14.38 3.836 16.376 5.932 1.00 12.50 3.593 15.907 7.302 1.00 18.91 2.233 16.385 7.818 1.00 17.20 1.228 15.959 6.895 1.00 21.04 2.207 17.905 7.935 1.00 19.65 3.631 14.391 7.375 1.00 19.00 4.022 13.822 8.414 1.00 21.72 3.227 13.766 6.258 1.00 18.63 3.239 12.330 6.113 1.00 19.81 2.562 11.959 4.811 1.0024.17 3.364 12.403 3.595 1.00 34.44 2.692 12.102 2.262 1.00 40.56 1.653 12.768 1.948 1.00 44.10 3.204 11.208 1.517 1.00 43.81 4.662 11.783 6.107 1.00 18.55 4.842 10.589 6.074 1.00 20.36 5.677 12.654 6.111 1.00 14.45 7.037 12.191 6.090 1.00 11.96 7.919 13.129 5.269 1.00 11.90 7.522 13.200 3.796 1.00 13.46 6.770 12.333 3.312 1.00 16.83 7.942 14.138 3.146 1.00 13.86 7.618 12.080 7.489 1.00 12.84 8.815 11.743 7.640 1.00 9.40 6.854 12.472 8.523 1.00 13.25 7.368 12.247 9.879 1.00 13.46 6.377 12.778 10.935 1.00 17.14 6.860 12.654 12.394 1.00 21.93 6.084 13.563 13.357 1.00 26.14 5.765 14.702 12.969 1.00 22.27 5.784 13.135 14.508 1.00 27.48 7.524 10.722 9.983 1.00 9.35 6.546 9.998 9.788 1.00 12.41 8.726 10.256 10.222 1.00 9.86 8.997 8.822 10.227 1.00 8.78 8.687 8.250 8.849 1.00 7.20 10.444 8.637 10.557 1.00 8.36 11.129 9.618 10.780 1.00 11.79 10.930 7.406 10.620 1.00 8.82 12.365 7.197 10.876 1.00 7.36 12.576 6.149 11.967 1.00 5.25 14.058 5.950 12.279 1.00 9.66 11.829 6.632 13.216 1.00 13.36 11.520 5.579 14.233 1.00 10.12 12.980 6.752 9.547 1.00 5.85 12.301 6.101 8.761 1.00 6.76 14.179 7.216 9.269 1.00 4.42 14.865 6.907 7.980 1.00 7.23 15.171 8.183 7.182 1.00 6.83 13.929 8.853 6.706 1.00 8.61 13.203 9.680 7.591 1.00 5.73 11.959 10.169 7.242 1.00 8.65 13.378 8.552 5.435 1.00 5.92 12.118 9.046 5.095 1.00 6.08 11.411 9.853 6.010 1.00 8.14 10.125 10.288 5.715 1.00 6.40 16.156 6.236 8.237 1.00 2.00 16.988 6.765 8.973 1.00 8.00 16.316 5.060 7.681 1.00 5.92 17.574 4.313 7.849 1.00 4.34 17.276 2.846 8.207 1.00 8.38 16.579 2.690 9.499 1.00 9.99 17.303 2.497 10.645 1.00 6.06 15.190 2.725 9.551 1.00 13.30 16.642 2.328 11.868 1.00 10.61 14.523 2.562 10.757 1.00 14.04 15.261 2.361 11.919 1.00 8.48 17.698 4.278 5.518 1.00 2.51 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02 542 -171-

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790 N GYS L88 792 CA CYS L 88 793 GB GYS L 88 794 SG GYS L 88 795 C GYS L88 796 0 GYS L 88 797 N ALA L89 799 CA ALA L 89 800 GB3 ALA L 89 801 C ALA L 89 802 0 ALA L89 803 N LEUJL 90 805 GA LEU L 90 806 GB LEU L 90 807 CG LEU L 90 808 CD I LEU L 90 809 GD2 LEU L 90 810 C LEUL 90 811 0 LEU L 90 812 N TRPL 91 814 GA TRP L 91 815 GB3 TRP L 91 816 CG TRP L 91 817 CD2 TRP L 91 818 GE2 TRP L 91 819 GE3 TRP L 91 820 CD1 TRP L 91 821 NEI TRP L 91 823 GZ2 TRP L 91 824 CD3TRP L 91 825 GH2 TRP L 91 826GC TRPL 91 827 0 TRP L 91 828 N TYR L 92 830 CA TYR L 92 831 GB3 TYR L 92 832 CG TYR L 92 833 GD1 TYR L 92 834 GEI TYR L 92 835 CD2TYRL 92 836 GE2 TYR L 92 837 CZ TYR L 92 838 OH TYR L 92 840 C TYR L 92 841 0 TYR L 92 842 N SER L 93 844 GA SER L 93 845 GB SER L 93 846 OG SER L 93 848 C SER L 93 849 0 SER L 93 850 N ASN L94 852 GA ASN L 94 853 GB ASN L 94 854 CG ASN L 94 855 ODI ASN L 94 856 ND2 ASN L 94 859 C ASN L 94 860 0 ASN L 94 861 N HIS L 95 863 GA HIS L 95 864 GB3 HIS L 95 865 CG 1HSL 95 866 GD2 HIS L 95 867 NDI HIS L 95 869 GEl HIS L 95 870 NE2 HIS L 95 872 C HIS L 95 873 0 HIS L 95 874 N TRP L96 876 CA TRP L 96 877 GB TRP L 96 19.647 4.308 6.639 1.00 5.93 20.437 4.146 5.446 1.00 9.35 21.402 5.306 5.236 1.00 5.49 22.756 5.378 6.415 1.00 15.50 21.214 2.859 5.589 1.00 8.53 21.502 2.427 6.714 1.00 8.84 21.496 2.220 4.494 1.00 8.42 22.252 0.975 4.532 1.00 8.94 21.301 -0.198 4.197 1.00 6.42 23.390 1.092 3.510 1.00 11.22 23.172 1.603 2.416 1.00 10.12 24.596 0.666 3.877 1.00 12.71 25.735 0.737 2.984 1.00 12.28 26.856 1.594 3.591 1.00 13.85 26.572 3.096 3.773 1.00 10.32 27.881 3.801 4.146 1.00 7.96 25.963 3.678 2.485 1.00 10.49 26.279 -0.668 2.683 1.00 14.32 26.363 -1.520 3.607 1.00 14.08 26.664 -0.881 1.385 1.00 10.21 27.175 -2.175 0.892 1.00 9.56 26.710 -2.415 -0.556 1.00 13.24 27.344 -3.582 -1.305 1.00 16.93 26.959 -5.000 -1.258 1.00 18.28 27.643 -5.656 -2.300 1.00 18.63 26.093 -5.774 -0.450 1.00 18.52 28.238 -3.469 -2.337 1.00 18.74 28.401 -4.692 -2.918 1.00 18.84 27.502 -7.049 -2.570 1.00 17.39 25.947 -7.1.55 -0.717 1.00 20.45 26.658 -7.779 -1.778 1.00 18.96 28.657 -2.194 0.947 1.00 8.96 29.308 -1.254 0.489 1.00 9.38 29.194 -3.229 1.552 1.00 9.41 30.624 -3.377 1.642 1.00 10.88 31.083 -3.349 3.115 1.00 13.13 30.867 -2.023 3.840 1.00 12.25 29.721 -1.780 4.606 1.00 15.61 29.514 -0.552 5.234 1.00 11.01 3 1.808 -1.003 3.741 1.00 14.35 31.607 0.208 4.358 1.00 12.95 30.464 0.437 5.090 1.00 11.34 30.246 1.701 5.613 1.00 14.51 31.048 -4.687 0.967 1.00 15.14 31.339 -5.693 1.650 1.00 14.53 31.013 -4.663 -0.383 1.00 16.81 3 1.449 -5.786 -1.249 1.00 18.41 32.878 -6.169 -0.907 1.00 19.53 33.736 -5.094 -1.258 1.00 25.55 30.564 -7.029 -1.238 1.00 20.20 30.249 -7.587 -2.322 1.00 17.43 30.202 -7.492 -0.025 1.00 19.09 29.415 -8.690 0.109 1.00 19.31 30.341 -9.916 0.037 1.00 18.06 31.359 -9.928 1.153 1.00 22.80 31.378 -9.025 2.026 1.00 22.03 32.210 -10.949 1.157 1.00 21.52 28.595 -8.688 1.403 1.00 20.27 28.147 -9.737 1.863 1.00 22.39 28.396 -7.508 1.999 1.00 19.53 27.529 -7.400 3.161 1.00 18.65 28.237 -7.853 4.407 1.00 16.28 29.404 -7.005 4.792 1.00 19.96 30.622 -6.861 4.235 1.00 17.79 29.430 -6.22 1 5.93 8 1.00 20.98 30.606 -5.630 6.085 1.00 22.66 3 1.326 -6.0 18 5.055 1.00 20.00 27.016 -5.983 3.353 1.00 17.00 27.555 -5.053 2.798 1.00 16.62 25.973 -5.841 4.146 1.00 15.07 25.375 -4.539 4.379 1.00 13.84 23.874 -4.536 4.055 1.00 12.09 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -172-

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878 879 880 881 882 883 885 886 887 888 889 890 892 893 894 895 896 897 898 900 901 902 903 904 905 906 907 908 909 910 912 913 914 915 917 918 919 920 922 923 924 925 927 928 929 931 932 933 934 936 937 938 939 940 941 945 946 947 949 950 951 952 953 954 955 956 958 959 960 962 963 964 CG TRP L 96 CD2 TRP L 96 CE2 TRP L 96 CE3 TRP L 96 CDI TRP L 96 NEI TRP L 96 CZ2 TRP L 96 CZ3 TRP L 96 CH2 TRP L 96 C TRP L96 0 TRP L96 N VAL L97 CA VAL L 97 GB VAL L 97 CG IVAL L 97 CG2 VAL L 97 C VAL L 97 O VAL L97 N PHE L98 CA PHE L 98 CB PHE L 98 CG PHE L 98 CDI PHE L 98 CD2 PHE L 98 GEl PHE L 98 CE2 PHE L 98 CZ PHE L 98 C PHE L 98 O PHE L98 N GLY L99 CA GLY L 99 C GLY L99 0 GLY L 99 N GLY L 100 CA GLY L 100 C GLY L 100 0 GLY L 100 N GLYL 101 CA GLY L 101 C GLY L 101 0 GLYL 101 N THR L 102 CA THR L 102 GB THR L 102 OGI THRL 10: CG2 THR L 102 C THR L 102 0 THR L 102 N LYS L 103 CA LYS L 103 GB LYS L 103 CG LYS L 103 CD LYS L 103 CE LYS L 103 NZ LYS L 103 C LYS L 103 O LYS L 103 N LEU L 104 CA LEU L 104 GB LEU L 104 CG LEU L 104 CDI LEU L 10~ CD2 LEU L 10~ C LEU L 104 '0 LEULI104 N THRLI105 CA THR L105 GB THR L105 OGI THRL 10 CG2 THRL 10 C THR L 105 0O TFR LI105 23.538 -4.737 2.603 1.00 14.83 23.352 -3.708 1.608 1.00 12.10 22.935 -4.340 0.424 1.00 13.36 23.490 -2.310 1.610 1.00 11.19 23.243 -5.913 1.998 1.00 15.53 22.883 -5.675 0.705 1.00 14.17 22.659 _3.631 -0.762 1.00 9.46 23.208 -1.605 0.441 1.00 7.52 22.800 -2.264 -0.725 1.00 11.56 25.495 -4.170 5.810 1.00 14.61 25.427 -5.064 6.666 1.00 12.87 25.684 -2.861 6.040 1.00 11.97 25.622 -2.286 7.380 1.00 13.35 26.975 -1.797 7.840 1.00 12.63 26.871 -1.164 9.220 1.00 14.09 27.888 -3.005 7.873 1.00 8.66 24.605 -1.151 7.396 1.00 14.93 24.590 -0.3 14 6.485 1.00 9.72 23.668 -1.219 8.353 1.00 13.01 22.630 -0.221 8.460 1.00 12.29 21.310 -0.843 8.887 1.00 9.91 20.504 -1.468 7.803 1.00 7.44 20.808 -2.728 7.341 1.00 9.14 19.386 -0.836 7.316 1.00 6.37 20.000 -3.337 6.425 1.00 6.90 18.560 -1.438 6.388 1.00 8.01 18.866 -2.696 5.939 1.00 7.78 23.038 0.846 9.456 1.00 11.91 23.874 0.594 10.318 1.00 11.43 22.533 2.062 9.247 1.00 14.08 22.804 3.151 10.148 1.00 12.11 21.820 3.098 11.296 1.00 11.79 20.893 2.304 11.265 1.00 10.46 22.005 3.957 12.289 1.00 12.00 21.125 3.950 13.458 1.00 8.79 19.739 4.511 13.254 1.00 9.23 18.840 4.293 14.098 1.00 12.86 19.513 5.213 12.163 1.00 7.60 18.185 5.779 11.930 1.00 4.00 18.156 7.209 12.445 1.00 7.52 18.921 7.549 13.417 1.00 7.76 17.414 8.053 11.698 1.00 8.12 17.192 9.492 12.014 1.00 7.96 17.613 10.425 10.805 1.00 7.52 19.020 10.319 10.576 1.00 4.45 17.266 11.885 11.056 1.00 4.44 15.707 9.657 12.212 1.00 10.01 14.965 9.257 11.330 1.00 11.13 15.221 10.188 13.349 1.00 10.41 13.779 10.404 13.436 1.00 11.36 13.226 10.449 14.887 1.00 14.52 11.770 11.006 14.917 1.00 16.54 11.191 11.143 16.337 1.00 12.70 9.718 11.536 16.299 1.00 14.64 8.869 10.602 15,451 1.00 17.17 13.446 11.719 12.778 1.00 10.60 14.022 12.721 13.143 1.00 12.19 12.508 11.730 11.847 1.00 9.69 12.168 12.978 11.228 1.00 11.35 12.128 12.887 9.693 1.00 9.61 11.734 14.219 9.032 1.00 10.81 4 12.879 15.223 9.204 1.00 2.00 4 11.370 13.998 7.591 1.00 10.86 10.849 13.494 11.718 1.00 10.04 9.857 12.786 11.669 1.00 16.01 10.832 14.730 12.221 1.00 11.71 9.581 15.367 12.551 1.00 7.07 9.634 16.082 13.932 1.00 9.46 5 9.752 15.104 14.961 1.00 12.27 5 8.383 16.936 14.168 1.00 2.15 9.232 16.415 11.493 1.00 7.56 10.043 17.245 11.158 1.00 9.71 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -173-

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965 967 968 969 970 971 972 973 975 976 977 978 979 980 981 982 984 985 986 987 989 990 991 993 994 995 997 998 999 1000 1001 1002 1003 1004 1005 1007 1008 1009 1010 1011 1012 1016 101'7 1018 1 020 1021 1022 1 024 1 025 ION2 1 021 I 02 1 03( 103: 103: 1 03~ 1 03~ 1 03~ 103' 103~ 103' 1041 104 104.

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104 104 104 104 105 105 105 N VAL L 106 CA VAL L 106 GB VAL L 106 CG I VAL L 106 CG2 VAL L 106 C VAL L 106 O VAL L 106 N LEULI106A CA LEULI106A CB LEU L 106A CG LEU L 106A CD I LEU L 106A CD2 LEU L 106A C LEULI106A O LEULI106A N GLY L 107 CA GLY L 107 C GLY L 107 O GLY L 107 N SERI, 108 CA SER L 108 GB SER L 108 OG SER L 108 C SERL, 108 O SERI, 108 N GLU L 109 CA GLU L 109 GB GLUL. 109 CG GLU L 109 CD GLU L 109 OE1I GLU L 109 0E2 GLU L 109 C GLU L 109 O GLU L 109 N LYSL 110 CA LYS L 110 GB LYS L 110 CG LYS L 110 CD LYS L 110 CE LYS L 110 NZ LYS L 110 C LYSLIIO 0~ LYSLIIO N SERLIII ICA SER L IlIl GB SER L I111 OG SERL III ~C SERLIII 0O SERLIlI ~N SERL 112 ICA SERL 112 CB SERI, 112 OG SER L 112 C SERLI112 3 0 SERLI112 t N PRO L113 5 CD PRO L 113 6 CA PRO L 113 7 GB PRO L 113 8 CG PRO L 113 9 C PRO L113 0 O PROLI113 1 N SER L 114 3 CA SER L 114 4 GB SER L 114 5 OG SER L 114 7 C SERLI114 8 0 SERLI114 9 N VAL L115 1 CA VAL L 115 2GCB VAL L 115 3 CGI VAL LIII 8.045 16.320 10.958 1.00 9.73 7.502 17.366 10.095 1.00 11.58 7.077 16.862 8.710 1.00 9.06 6.497 18.013 7.899 1.00 6.52 8.310 16.244 8.006 1.00 10.40 6.301 17.925 10.847 1.00 11.09 5.207 17.320 10.868 1.00 13.54 6.577 19.053 11.520 1.00 12.43 5.642 19.701 12.379 1.00 12.13 6.113 21.124 12.661 1.00 9.12 7.487 21.216 13.339 1.00 7.72 7.977 22.640 13.275 1.00 9.05 7.425 20.710 14.802 1.00 6.98 4.312 19.671 11.757 1.00 13.07 4,079 20.351 10.783 1.00 18.75 3.459 18.809 12.289 1.00 14.91 2.110 18.678 11.759 1.00 16.40 1.061 19.131 12.754 1.00 15.29 -0.116 18.916 12.541 1.00 16.64 1.523 19.749 13.846 1.00 18.60 0.654 20.252 14.900 1.00 18.91 0. 113 19.115 15.777 1.00 21.02 1.150 18.546 16.571 1.0027.15 1.466 21.163 15.756 1.00 17.58 2.689 21.205 15.631 1.00 17.99 0.796 21.813 16.676 1.00 17.83 1.428 22.764 17.513 1.00 16.58 0.331 23.558 18.218 1.00 21.42 -0.493 24.469 17.312 1.00 26.54 -1.293 23.737 16.238 0.50 27.76 1.724 22.605 16.512 0.50 28.73 -1.495 24.302 15.113 0.50 26.82 2.297 22.034 18.519 1.00 17.20 1.920 20.963 18.969 1.00 14.41 3.437 22.590 18.885 1.00 16.72 4.265 21.907 19.855 1.00 20.99 5.610 22.576 20.013 1.00 22.20 6.485 22.357 18.796 1.00 24.75 7.790 23.103 18.889 1.00 25.15 8.528 23.039 17.563 1.00 30.78 9928 23.555 17.661 1.00 32.12 3.557 21.790 21.192 1.00 21.68 2.753 22.651 21.562 1.00 22.35 3.836 20.687 21.879 1.00 22.71 3.205 20.372 23.162 1.00 21.05 2.148 19.308 22.923 1.00 22.18 1.301 19.149 24.046 1.00 23.73 4.276 19.861 24.147 1.00 21.55 5.085 18.989 23.799 1.00 21.72 4.347 20.473 25.339 1.00 19.80 5.3 17 20.077 26.346 1.00 17.43 5.389 21.174 27.397 1.00 20.85 6.341 22.165 27.033 1.00 29.98 4.918 18.749 26.998 1.00 14.25 3.726 18.427 27.069 1.00 19.12 5.860 17.946 27.492 1.00 10.92 7.314 18.159 27.548 1.00 7.81 5.491 16.696 28.117 1.00 12.79 6.794 15.982 28.227 1.00 8.93 7.734 17.088 28.499 1.00 9.20 4.824 16.896 29.483 1.00 13.59 5.181 17.799 30.251 1.00 13.35 3.810 16.116 29.741 1.00 15.55 3.233 16.066 31.058 1.00 15.08 1.734 15.863 30.975 1.00 17.33 1.142 15.947 32.273 1.00 25.09 3.904 14.922 31.825 1.00 16.29 3.795 13.732 31.458 1.00 15.53 4.628 15.301 32.864 1.00 12.98 5.425 14.374 33.668 1.00 12.33 6.750 15.005 33.997 1.00 6.39 7.689 13.957 34.586 1.00 3.44 SUBSTITIUTI SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -174-

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1054 1055 1056 1057 1059 1060 1061 1063 1064 1065 1066 1068 1069 1070 1071 1072 1073 1074 1075 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1103 1104 1105 1 108 11 09 1111 1112 1113 1115 11V~ 112~ 1112 1121 112 112: 112' 112; 112 I113i 113 113: 113 113 113 GG2 VAL L 115 C VAL L115 0 VAL L 115 N THRL 116 CA THR L 116 GB THR L 116 OGI THRL 116 CG2 THR L 116 C THRL 116 O THR L 116 N LEU L 117 GA LEU L 117 GB LEU L 117 CG LEU L 117 CDI LEU L 117 CD2 LEU L 117 C LEU L 117 0 LEU L 117 N PHE L 118 CA PHE L 118 GB PHE L 118 CG PHE L 118 CDI PHE L 118 GD2 PHE L 118 GEl PHE L 118 CE2 PHE L 118 CZ PHE L 118 C PHEL 118 O PHE L 118 N PRO L 119 CD PRO L 119 CA PRO L 119 GB PRO L 119 CG PRO L 119 C PRO L 119 0 PRO L 119 N PRO L 120 CD PRO L 120 GA PRO L 120 GB PRO L 120 GG PRO L 120 C PRO L 120 O PRO L 120 N SER L 121 GA SER L 121 GB SER L 121 *OG SER L 121 C SER L121 0 SERLI121 IN SER L122 CA SER L 122 CGB SER L 122 OG SER L 122 CG SER L122 0O SER L122 ~N ALA L123 CA ALA L 123 GB ALA L 123 1 C ALA L 123 Z 0 ALA L 123 3 N GLULI124 5 CA GLU L 124 6 GB GLU L 124 7 CG GLU L 124 8 CD GLU L 124 9 OE1IGLU L 124 0 0E2 GLU L 124 1 G GLU L 124 2 0 GLULI124 3 N LEULI125 5 CA LEU L 125 6 CB LEU L 125 7.329 15.649 32.742 1.00 9.96 4.770 13.999 35.000 1.00 13.58 4.200 14.837 35.678 1.00 13.43 4.877 12.751 35.360 1.00 12.99 4.395 12.291 36.646 1.00 11.92 3.063 11.544 36.555 1.00 10.15 2.131 12.353 35.844 1.00 5.53 2.5 18 11.242 37.963 1.00 10.07 5.424 11.339 37.206 1.00 13.44 5.890 10.420 36.477 1.00 13.00 5.817 11.574 38.463 1.00 9.86 6.772 10.697 39.109 1.00 10.48 7.979 11.494 39.504 1.00 8.99 9.092 10.708 40.182 1.00 13.84 9.754 9.741 39.203 1.00 10.30 10. 103 11.683 40.772 1.00 17.17 6.129 9.969 40.328 1.00 9.98 5.449 10.575 41.149 1.00 12.16 6.314 8.676 40.398 1.00 9.99 5.728 7.871 41.449 1.00 9.51 4.868 6.756 40.872 1.00 6.53 3.648 7.209 40.167 1.00 6.03 2.533 7.617 40.889 1.00 4.85 3.574 7.148 38.760 1.00 3.25 1.345 7.947 40.244 1.00 6.00 2.398 7.484 38.118 1.00 2.00 1.272 7.881 38.861 1.00 3.81 6.816 7.225 42.272 1.00 9.33 7.836 6.726 41.745 1.00 9.88 6.624 7.227 43.591 1.00 9.00 5.458 7.837 44.283 1.00 7.59 7.582 6.622 44.541 1.00 8.55 7.173 7.283 45.851 1.00 9.62 5.685 7.380 45.703 1.00 9.04 7.379 5.121 44.603 1.00 4.72 6.383 4.647 44.105 1.00 6.50 8.311 4.363 45.159 1.00 3.79 9.661 4.784 45.473 1.00 6.28 8.158 2.910 45.301 1.00 6.76 9.507 2.416 45.767 1.00 9.39 10. 194 3.621 46.269 1.00 5.45 7.032 2.552 46.267 1.00 10.87 6.788 3.263 47.246 1.00 11.35 6.276 1.5 18 45.944 1.00 12.02 5.172 1.105 46.811 1.00 14.15 4.160 0.187 46.055 1.00 13.52 4.706 -1.083 45.758 1.00 14.31 5.737 0.4 15 48.061 1.00 15.89 6.916 0.005 48.087 1.00 14.68 4.923 0.342 49.116 1.00 15.71 5.363 -0.308 50.339 1.00 17.27 4.334 -0.057 51.448 1.00 17.69 3.023 -0.391 51.004 1.00 25.59 5.512 -1.801 50.069 1.00 14.07 6.481 -2.426 50.529 1.00 16.14 4.559 -2.338 49.272 1.00 11.63 4.558 -3.769 48.934 1.00 10.10 3.319 -4.106 48.130 1.00 13.01 5.828 -4.148 48.204 1.00 9.75 6.478 -5.134 48.560 1.00 6.87 6.253 -3.321 47.225 1.00 8.37 7.493 -3.602 46.545 1.00 7.57 7.789 -2.653 45.377 1.00 9.85 9.123 -2.992 44.703 1.00 9.19 9.466 -2.117 43.521 1.00 8.89 8.843 -1.079 43.377 1.00 11.65 10.370 -2.461 42.741 1.00 10.96 8.653 -3.537 47.482 1.00 8.44 9.501 -4.435 47.473 1.00 7.83 8.701 -2.484 48.325 1.00 10.06 9.842 -2.287 49.268 1.00 8.99 9.576 -1.049 50.147 1.00 6.82 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -175-

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1137 CG LEU L 125 1138 CD I LEU L 125 1139 CD2 LEU L 125 1140 C LEU L 125 1141 0 LEU L 125 1142 N GLULI126 1144 CA GLU L 126 1145 GB GLU L 126 1146 CG GLU L 126 1147 CD GLU L 126 1148 OE I GLU L 126 1149 0E2 GLU L 126 1150 C GLULI126 1151 0 GLU L 126 1152 N THR L 127 1154 CA THR L 127 1155 GB THR L 127 1156 OG ITHR L 127 1158 CG2 THR L 127 1159 C THRLI127 1160 0 THR L127 1161 N ASN L 128 1163 CA ASN L 128 1164 GB ASN L 128 1165 CG ASN L 128 1166 ODI ASN L 128 1167 ND2 ASN L 128 1170 C ASN L 128 1171 0 ASN L 128 1172 N LYS L 129 1174 GA LYS L 129 1175 GB LYS L 129 1176 CG LYS L 129 1177 CD LYS L 129 1178 CE LYS L 129 1179 NZ LYS L 129 1183 C LYS L 129 1184 0 LYS L 129 1185 N ALA L 130 1187 GA ALA L 130 1188 GB ALA L 130 1189 C ALA L 130 1190 0 ALA L 130 1191 N THR L 131 1193 GA THR L 131 1194 GB THR L 131 1195 OG ITHR L 131 1197 CG2 THR L 131 1198 C THR L 131 1199 0 THR L 131 1200 N LEU L 132 1202 CA LEU L 132 1203 GB LEU L 132 1204 GG LEU L 132 1205 CD I LEU L132 1206 GD2 LEU L 132 1207 C LEU L 132 1208 0 LEU L 132 1209 N VAL L 133 1211 CA VAL L 133 1212 GB VAL L 133 1213 CGI VAL L 133 1214 GG2 VAL L 133 1215 C VAL L 133 1216 0 VAL L 133 1217 N CYS L 134 1219 GA CYS L 134 1220 GB GYS L 134 1221 SG CYS L 134 1222 C GYS L 134 1223 0 GYS L 134 1224 N TH-RL 135 9.871 0.279 49.439 1.00 8.44 9.200 1.466 50.110 1.00 10.23 11.373 0.475 49.349 1.00 10.82 10.121 -3.494 50.150 1.00 7.68 11.288 -3.786 50.5 19 1.00 6.19 9.069 -4.188 50.506 1.00 9.15 9.227 -5.365 51.341 1.00 12.67 7.899 -6.020 51.519 1.00 15.98 6.888 -5.137 52.171 1.00 19.89 5.648 -5.907 52.484 1.00 22.91 5.696 -7.174 52.467 1.00 24.59 4.6 12 -5.254 52.744 1.00 26.87 10.169 -6.368 50.702 1.00 14.63 10.842 -7.132 51.421 1.00 12.25 10.179 -6.388 49.326 1.00 13.98 11.054 -7.312 48.549 1.00 13.13 10.542 -7.570 47.086 1.00 11.80 10.753 -6.412 46.267 1.00 10.21 9.068 -7.926 47.066 1.00 12.12 12.460 -6.775 48.453 1.00 12.72 13.266 -7.316 47.715 1.00 14.85 12.740 -5.706 49.208 1.00 13.49 14.045 -5.057 49.225 1.00 13.82 15.145 -6.048 49.663 1.00 19.63 15.125 -6.270 51.168. 1.00-23.79 14.932 -7.391 51.638 1.00 26.72 15.3 14 -5.191 51.937 1.00 25.77 14.399 -4.369 47.910 1.00 14.19 15.595 -4.130 47.597 1.00 13.24 13.354 4.000 47.173 1.00 17.87 13.501 -3.3 18 45.900 1.00 18.00 13.046 -4.229 44.745 1.00 22.35 13.7 16 -5.598 44.695 1.00 24.95 15.206 -5.464 44.537 1.00 28.22 15.848 -6.815 44.346 1.00 30.22 15.385 -7.425 43.073 1.00 34.30 12.666 -2.037 45.876 1.00 16.78 11.603 -1.956 46.464 1.00 15.40 13.165 -1.045 45.172 1.00 16.40 12.452 0.224 45.009 1.00 15.30 12.995 1.278 45.962 1.00 10.48 12.575 0.729 43.554 1.00 13.30 13.692 0.976 43.062 1.00 13.88 11.420 0.825 42.873 1.00 10.24 11.369 1.338 41.527 1.00 8.65 10.689 0.363 40.539 1.00 9.65 11.282 -0.953 40.646 1.00 10.61 10.801 0.902 39.092 1.00 8.13 10.568 2.603 41.513 1.00 4.73 9.464 2.621 42.019 1.00 7.42 11.149 3.647 40.968 1.00 5.79 10.449 4.904 40.787 1.00 8.20 11.386 6.086 41.075 1.00 7.00 11.799 6.378 42.544 1.00 9.11 12.650 5.258 43.104 1.00 6.00 12.609 7.678 42.596 1.00 8.20 9.976 4.970 39.341 1.00 7.07 10.743 4.665 38.440 1.00 10.93 8.742 5.331 39.116 1.00 7.44 8.234 5.363 37.756 1.00 7.69 6.923 4.598 37.629 1.00 5.71 6.392 4.690 36.194 1.00 5.28 7.145 3.138 38.022 1.00 10.59 7.970 6.779 37.300 1.00 8.68 7.296 7.541 37.962 1.00 8.54 8.448 7.117 36.140 1.00 12.17 8.204 8.457 35.595 1.00 9.67 9.558 9.120 35.346 1.00 8.40 9.463 10.812 34.680 1.00 10.83 7.451 8.308 34.295 1.00 9.67 8.004 7.706 33.371 1.00 10.89 6.195 8.745 34.238 1.00 6.29 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -176-

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1226 1227 1228 1230 1231 1232 1233 1235 1236 1237 1238 1239 1240 1241 1242 1244 1245 1246 1248 1249 1250 1251 1253 1254 1255 1256 1257 1258 1259 1260 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1274 1275 1276 1277 1278 1279 1280 1281 1282 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1295 1296 1297 1298 1300 1301 1302 1303 1304 1305 1306 1308 CA THR L 135 GB .THR L 135 OG I THR L 135 CG2 THR L 13 5 C THR L 135 O THRL 135 N ILE L 136 CA ILE L 136 GB ILE L 136 CG2 ILE L 136 CGI ILE L 136 CD ILE L 136 C ILE L 136 0 ILE L 136 N THRLI137 CA THR L 137 C1B THR L 137 001I THR L 137 CG2 THR L 137 C THRL 137 0 THRL 137 N ASP L 138 CA ASP L 138 GB3 ASP L 13 8 CG ASP L 138 ODI ASP L 138 OD2 ASP L 13 8 C ASP L 138 O ASP L 138 N PHE L 139 CA PHE L 139 GB3 PHE L 139 CG PHE L 139 CDI PHE L 139 CD2 PHE L 139 GEl PHE L 139 CE2 PHE L 139 CZ PHE L 139 C PHE L 139 0 PHE L 139 N TYR L 140 CA TYR L 140 CB TYR L 140 CG TYR L 140 CDlI TYR L 140 GEl TYR L 140 CD2 TYR L 140 CE2 TYR L 140 CZ TYR L 140 OH TYR L 140 C TYR L 140 O TYR L 140 N PRO L141 GD PRO L 141 CA PRO L 141 GB3 PRO L 141 G PRO L 141 C PROLI141 O PRO L 141 N GLY L 142 GA GLY L 142 C GLY L 142 0 GLY L 142 N VAL L 143 CA VAL L 143 GB VAL L 143 CGI VAL L 143 CG2 VAL L 143 C VAL L 143 O VAL L 143 N VAL L 144 CA VAL L 144 5.469 8.655 33.028 1.00 5.35 4.012 8.195 33.246 1.00 5.71 3.231 9.219 33.891 1.00 11.96 3.984 6.920 34.095 1.00 2.00 5.547 9.987 32.316 1.00 9.71 5.826 11.012 32.949 1.00 11.41 5.426 9.983 30.994 1.00 9.98 5.672 11.228 30.205 1.00 11.09 7.150 11.268 29.663 1.00 12.20 7.420 12.602 28.960 1.00 10.90 8.166 11.011 30.783 1.00 10.97 9.578 10.697 30.284 1.00 11.49 4.723 11.215 29.019 1.00 10.64 4.806 10.326 28.215 1.00 11.08 3.795 12.154 28.927 1.00 10.77 2.811 12.071 27.890 1.00 9.97 1.469 11.499 28.449 1.00 11.90 0.866 12.381 29.434 1.00 11.66 1.724 10.164 29.119 1.00 12.72 2.596 13.417 27.221 1.00 13.30 3.181 14.431 27.670 1.00 10.45 1.825 13.363 26.116 1.00 12.35 1.342 14.541 25.354 1.00 14.23 0.325 15.323 26.180 1.00 12.77 -0.778 14.452 26.713 1.00 16.64 -1.699 14.084 25.926 1.00 15.94 -0.734 14.127 27.929 1.00 16.10 2.407 15.499 24.869 1.00 12.96 2.181 16.698 24.879 1.00 13.42 3.568 15.004 24.439 1.00 15.33 4.590 15.914 23.899 1.00 12.61 5.988 15.685 24.488 1.00 13.93 6.452 14.249 24.550 1.00 17.51 6.016 13.407 25.571 1.00 14.06 7.344 13.747 23.599 1.00 18.44 6.450 12.114 25.644 1.00 15.91 7.781 12.440 23.674 1.00 17.97 7.331 11.616 24.701 1.00 19.08 4.671 15.822 22.398 1.00 14.58 4.364 14.779 2 1.822 1.00 13.97 5.003 16.967 21.771 1.00 14.53 5.221 17.043 20.3 17 1.00 15.96 3.934 17.281 19.554 1.00 9.65 4.165 17.225 18.059 1.00 17.09 4.137 16.015 17.390 1.00 18.26 4,377 15.939 16.022 1.00 18.78 4.445 18.376 17.3 14 1.00 17.33 4.691 18.309 15.948 1.00 17.98 4.650 17.083 15.318 1.00 19.92 4.861 17.000 13.970 1.00 21.97 6.157 18.195 20.052 1.00 14.90 5.831 19.286 20.462 1.00 17.79 7.343 18.0 14 19.373 1.00 17.44 8.353 19.083 19.188 1.00 18.49 7.859 16.742 18.793 1.00 16.51 9.251 17.124 18.303 1.00 16.41 9.134 18.569 18.033 1.00 18.35 7.977 15.581 19.781 1.00 17.49 8.147 15.784 21.000 1.00 16.25 7.918 14.379 19.234 1.00 16.47 8.090 13.192 20.037 1.00 17.96 9.530 12.886 20.377 1.00 17.11 9.975 11.757 20.259 1.00 20.37 10.292 13.854 20.777 1.00 17.91 11.632 13.552 21.210 1.0020.37 12.695 13.972 20.179 1.00 25.23 12.502 15.421 19.764 1.00 27.03 14.083 13.765 20.778 1.00 23.81 11.921 14.205 22.557 1.00 20.36 11.713 15.416 22.712 1.00 18.56 12.396 13.381 23.522 1.00 18.00 12.718 13.845 24.891 1.00 18.09 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB198/02542 -177-

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1309 GB VAL L 144 1310 CG1I VAL L 144 1311 CG2 VAL L 144 1312 C VAL L 144 1313 0 VAL L 144 1314 N THR L 145 1316 GA THR L 145 1317 GB THR L 145 1318 OG1ITHR L 145 1320 GG2 THR L 145 1321 C THR L 145 1322 0 THR L 145 1323 N VAL L 146 1325 GA VAL L 146 1326 GB VAL L 146 1327 CG1IVAL L 146 1328 GG2 VAL L 146 1329 C VAL L 146 1330 0 VAL L 146 1331 N ASP L 147 1333 CA ASP L 147 1334 GB ASP L 147 1335 CG ASP L 147 1336 ODI ASP L 147 1337 0D2 ASP L 147 1338 C ASP L 147 1339 0 ASP L 147 1340 N TRP L 148 1342 CA TRP L 148 1343 GB TRP L 148 1344 CG TRP L 148 1345 CD2 TRP L 148 1346 CE2 TRP L 148 1347 CE3 TRP L 148 1348 CD1ITRP L 148 1349 NEI1TRP L 148 1351 GZ2 TRP L 148 1352 GZ3 TRP L 148 1353 CH2 TRP L 148 1354 C TRP L 148 1355 0 TRP L 148 1356 N LYS L 149 1358 CA LYS L 149 1359 GB LYS L 149 1360 CG LYS L 149 1361 GD LYS L 149 1362 GE LYS L 149 1363 NZ LYS L 149 1367 C LYS L 149 1368 0 LYS L 149 1369 N VAL L 150 1371 GA VAL L 150 1372 GB VAL L 150 1373 CG1VAL L 150 1374 GG2 VAL L 150 1375 C VAL L 150 1376 0 VAL L 150 1377 N ASP L 151 1379 GA ASP L 151 1380 GB ASP L 151 1381 GG ASP L 151 1382 OD IASP L 151 1383 OD2 ASP L 151 1384 C ASP L 151 1385 0 ASP L 151 1386 N GLY L 152 1388 GA GLY L 152 1389 C GLY L 152 1390 0 GLY L 152 1391 N THR L 15 3 1393 GA THR L 153 1394 GB THR L 153 11.582 13.532 25.913 1.00 15.31 10.334 14.306 25.602 1.00 13.05 11.282 12.036 25.925 1.00 15.08 13.941 13.125 25.397 1.00 17.23 14.189 11.991 24.992 1.00 15.86 14.744 13.798 26.217 1.00 16.98 15.795 13.107 26.924 1.00 17.36 17.233 13.739 26.775 1.00 22.21 17.569 14.568 27.897 1.00 22.36 17.366 14.530 25.486 1.00 19.06 15.378 13.091 28.392 1.00 19.55 14.813 14.077 28.871 1.00 15.45 15.578 11.946 29.064 1.00 19.67 15.185 11.787 30.463 1.00 17.75 14.353 10.502 30.668 1.00 15.39 14.100 10.249 32.158 1.00 16.28 13.051 10.633 29.945 1.00 12.45 16.429 11.709 3 1.327 1.00 18.57 17.354 10.986 31.018 1.00 20.82 16.442 12.464 32.396 1.00 16.64 17.574 12.502 33.271 1.00 16.87 18.284 13.862 33.104 1.00 22.38 19.067 13,963 31.791 1.0025.15 20.153 13.344 31.712 1.00 25.53 18.586 14.651 30.843 1.00 24.06 17.104 12.315 34.710 1.00 13.63 16.220 13.032 35.167 1.00 17.40 17.676 11.358 35.399 1.00 12.32 17.287 11.061 36.792 1.00 8.34 17.209 9.521 36.985 1.00 7.75 16.010 8.879 36.377 1.00 9.41 14.738 8.705 37.013 1.00 7.75 13.895 8.079 36.088 1.00 9.98 14.241 9.019 38.304 1.00 11.38 15.889 8.362 35.116 1.00 5.30 14.627 7.895 34.964 1.00 10.25 12.576 7.750 36.379 1.00 10.62 12.929 8.690 38.606 1.00 8.84 12.106 8.061 37.642 1.00 9.81 18.328 11.611 37.741 1.00 10.55 19.526 11.572 37.440 1.00 11.66 17.904 12.113 38.891 1.00 10.12 18.858 12.592 39.860 1.00 10.24 18.985 14.121 39.739 1.00 9.85 1.9.879 14.486 38.551 1.00 15.84 19.786 15.934 38.146 1.00 20.45 20.968 16.327 37.251 1.00 25.03 21.280 15.297 36.192 1.00 26.83 18.508 12.120 41.265 1.00 9.83 17.341 11.959 41.593 1.00 8.42 19.554 11.804 42.034 1.00 12.70 19.402 11.385 43.438 1.00 13.13 19.928 .9.952 43.602 1.00 14.08 20.396 9.706 45.001 1.00 9.65 18.814 8.969 43.242 1.00 12.12 20.157 12.35 1 44.369 1.00 13.82 21.401 12.411 44.353 1.00 11.33 19.404 13.120 45.185 1.00 15.72 20.015 14.144 46.055 1.00 13.64 20.890 13.514 47.148 1.00 17.87 20.098 12.911 48.300 1.00 18.72 18.864 13.024 48.312 1.00 17.99 20.716 12.318 49.203 1.00 20.12 20.831 15.094 45.207 1.00 12.12 21.950 15.539 45.548 1.00 14.72 20.291 15.366 44.072 1.00 13.53 20.915 16.310 43.184 1.00 15.70 21.962 15.737 42.261 1.00 16.31 22.367 16.417 41.334 1.00 17.83 22.402 14.503 42.469 1.00 18.56 23.470 13.953 41.618 1.00 18.43 24.506 13.187 42.455 1.00 19.60 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -178-

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1395 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1409 1410 1411 1412 1413 1414 1415 1417 1418 1419 1421 1422 1423 1424 1426 1427 1428 1429 1430 1431 1434 1435 1436 1438 1439 1440 1441 1443 1444 1445 1446 1447 1448 1449 1450 1452 1453 1454 1455 1456 1457 1458 1459 1460 1462 1463 1464 1466 1467 1468 1469 1471 1472 1473 1475 1476 1477 1478 1 480 1481 OG I THR L 153 CG2 THR L 153 C THR L 153 TI-R L 153 N PRO L 154 GD PRO L 154 GA PRO L 154 GB PRO L 154 CG PRO L 154 C PRO L 154 O PRO L 154 N VAL L 155 GA VAL L 155 GB VAL L 155 GI VAL L 155 CG2 VAL L 155 C VAL L 155 O VAL L 155 N THR L 156 GA THRL 156 CB THR L 156 OG I THR L 156 GG2 THR L 156 C THR L 156 O THR L 156 N GLN L 157 CA GLN L 157 GB GLN L 157 CG GLN L 157 GD GLN L 157 OE1 GLN L 157 NE2 GLN L 157 G GLN L 157 O GLN L 157 N GLY L 158 GA GLY L 158 G GLY L 158 0 GLY L 158 N MET L 159 GA MET L 159 GB MET L 159 GG MET L 159 SD MET L 159 GE MET L 159 C MET L 159 O MET L 159 N GLU L 160 GA GLU L 160 GB GLU L 160 GG GLU L 160 GD GLU L 160 OEI GLU L 160 0E2 GLU L 160 C GLU L 160 0 GLU L 160 N THR L 161 GA THR L 161 GB THR L 161 OG I THR L 161 GG2 THR L 161 C THR L 161 O THR L 161 N THR L 162 CA THR L 162 GB THR L 162 001I THR L 162 CG2 THR L 162 C THRLI162 '0 THRLI162 N ALALI163 GA ALA L 163 GB ALA L 163 23.922 11.995 42.976 1.00 25.85 24.950 14.035 43.642 1.00 23.47 22.898 13.092 40.464 1.00 18.68 2 1.884 12.405 40.595 1.00 18.23 23.513 13.163 39.280 1.00 18.73 24.731 13.947 38.974 1.00 19.95 23.033 12.415 38.103 1.00 18.94 23.849 13.028 36.966 1.00 18.59 25.139 13.351 37.660 1.00 18.89 23.197 10.907 38.242 1.00 15.33 24.228 10.437 38.673 1.00 16.30 22.154 10.137 37.959 1.00 16.59 22.332 8.695 38.029 1.00 19.40 21.085 7.954 38.622 1.00 19.34 20.152 8.939 39.284 1.00 18.37 20.364 7.120 37.576 1.00 18.74 22.758 8.134 36.630 1.00 21.02 22.403 8.683 35.565 1.00 19.02 23.590 7.103 36.649 1.0022-.42 24.084- 6.518 35.421 1.0023.32 25.572 6.776 35.297 1.00 23.16 26.227 6.308 36.480 1.00 25.01 25.825 8.259 35.140 1.00 25.87 23.868 5.030 35.422 1.00 25.17 24.366 4.330 34.557 1.00 28.73 23.119 4.542 36.379 1.0023.46 22.911 3.142 36.481 1.0023.50 23.955 2.603 37.417 1.0029.55 24.082 1.104 37.377 1.00 37.55 25.314 0.646 38.117 1.0043.33 25.777 1.3 17 39.059 1.00 43.65 25.865 -0.493 3 7.685 1.00 45.54 21.5 18 2.866 37.002 1.00 19.92 21.011 3.632 37.773 1.00 18.81 20.889 1.810 36.538 1.00 18.99 19.556 1.472 37.015 1.00 20.19 18.384 2.250 36.379 1.00 22.36 17.258 2.080 36.791 1.00 22.31 18.624 3.105 35.392 1.0024.81 17.529 3.817 34.750 1.00 22.88 17.796 5.327 34.682 1.00 23.15 18.824 5.803 33.688 1.00 26.34 20.5 13 5.742 34.305 1.00 34.44 21.012 4.154 33.640 1.00 31.53 17.266 3.230 33.363 1.0023.01 18.173 2.800 32.688 1.0024.49 16.020 3.191 32.958 1.00 19.49 15.666 2.598 31.715 1.00 19.70 15.367 1.118 31.969 1.00 21.50 14.549 0.400 30.931 1.00 24.34 15.309 0.068 29.669 1.00 30.12 16.548 -0.128 29.774 1.00 28.32 14.660 0.005 28.567 1.00 30.69 14.484 3.332 31.146 1.00 19.64 13.438 3.390 31.774 1.00 18.31 14.663 3.904 29.945 1.00 20.21 13.606 4.711 29.285 1.00 18.39 14.152 6.135 28.966 1.00 19.35 14.634 6.725 30.180 1.00 15.43 13.085 7.028 28.361 1.00 13.84 13.089 4.048 27.992 1.00 18.90 13.855 3.391 27.282 1.00 18.53 11.776 4.198 27.724 1.00 17.02 11.162 3.604 26.558 1.00 14.46 9.771 3.023 26.877 1.00 9.31 8.882 4.060 27.343 1.00 8.44 9.890 1.934 27.939 1.00 8.50 11.080 4.614 25.407 1.00 15.09 11.086 5.838 25.608 1.00 14.93 11.055 4.106 24.190 1.00 12.96 11 .045 4.973 23.048 1.00 10.76 11.436 4.206 21.765 1.00 15.08 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -179-

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1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1493 1494 1495 1497 1498 1499 1501 1502 1503 1504 1505 1.506 1510 1511 1512 1514 1515 1516 1517 1518 1519 1522 1523 1524 1526 1527 1528 1530 1531 1532 1534 1535 1536 1537 1538 1541 1542 1543 1545 1546 1547 1548 1549 1552 1553 1554 1556 1557 1558 1559 1560 1561 1565 1566 1567 1569 1570 1571 1572 1573 1574 1575 C ALA L 163 O ALA L 163 N PRO L 164 CD PRO L 164 CA PRO L 164 CB PRO L 164 CG PRO L 164 C PRO L 164 0 PRO L 164 N SER L 165 CA SER L 165 GB SER L 165 OG SER L 165 C SER L 165 O SER L 165 N LYS L 166 CA LYS L 166 GB LYS L 166 CG LYS L 166 CD LYS L 166 CE LYS L 166 NZ LYS L 166 C LYS L 166 O LYS L 166 N GLN L 167 CA GLN L 167 CB GLN L 167 CG GLN L 167 CD GLN L 167 OE1I GLN L 167 NE2 GLN L 167 C GLN L 167 O GLN L 167 N SER L 168 CA SERL 168 GB SER L 168 OG SER L 168 C SERL 168 O SERL 168 N ASN L 169 CA ASN L 169 GB ASN L 169 CG ASN L 169 ODI ASN L 169 ND2 ASN L 169 C ASN L 169 O ASN L 169 N ASN L 170 CA ASN L 170 GB ASN L 170 CG ASN L 170 OD I ASN L 170 ND2 ASN L 170 C ASN L 170 0 ASN L 170 N LYS L 171 9.711 8.730 9.639 10.782 8.372 8.786 10.083 5.563 22.914 4.859 22.998 6.885 22.727 7.823 22.601 7.584 22.589 8.958 22.082 9.139 22.783 1.00 8.59 1.00 11.96 1.00 11.37 1.00 12.89 1.00 11.21 1.00 11.04 1.00 11.07 7.506 6.838 21.620 1.00 12.84 8.003 6.161 20.722 1.00 17.44 6.241 6.881 21.819 1.00 14.17 5.355 6.186 20.922 1.00 16.08 4.917 4.813 21.480 1.00 17.01 3.832 4.924 22.378 1.00 22.35 4.220 7.095 20.722 1.00 15.78 3.950 7.910 21.590 1.00 15.19 3.597 7.0 13 19.588 1.00 17.84 2.582 7.984 19.248 1.00 19.88 2.391 8.017 17.746 1.00 22.34 2.325 9.408 17.139 1.0021.36 2.273 9.317 15.606 1.0025.05 2.601 10.656 14.965 0.01 22.27 2.538 10.600 13.475 0.01 22.15 1.282 7.698 19.914 1.00 21.48 0.893 6.541 20.046 1.00 23.82 0.624 8.768 20.360 1.00 20.46 -0.706 8.663 20.929 1.00 19.43 -0.959 9.744 2 1.957 1.00 19.09 0.073 9.829 23.070 1.00 13.91 173 10.995 24.012 1.00 12.43 0.487 11. 132 25.070 1.00 12.78 -1.121 11.854 23.651 1.00 12.35 -1.691 8.864 19.808 1.00 20.58 -1.337 9.390 18.777 1.00 19.43 -2.917 8.477 20.015 1.0024.20 -3.932 8.620 18.983 1.00 28.22 -5.283 8.203 19.551 1.00 29.04 -5.480 8.808 20.824 1.00 34.62 -4.005 10.061 18.471 1.00 30.48 -4.452 10.32 1 17.33 1 1.00 34.63 -3.569 11.002 19.285 1.00 26.12 -3.650 12.370 18.871 1.00 25.93 -4.070 13.284 20.021 1.00 29.63 -3.094 13.375 21.169 1.00 29.04 -2.067 12.703 21.217 1.00 31.37 -3.431 14.220 22.100 1.00 31.92 -2.362 12.794 18.299 1.00 25.86 -2.067 13.967 18.208 1.00 26.70 -1.592 11.830 17.924 1.00 23.96 -0.328 12.075 17.287 1.00 23.68 -0.560 12.714 15.923 1.00 25.27 -1.128 11.651 14.991 1.0028.14 -0.430 10.692 14.635 1.00 30.35 -2.403 11.769 14.642 1.00 29.66 0.675 12.826 18.113 1.00 22.90 1.705 13.241 17.610 1.0025.60 0.396 13.038 19071 1.00 21.22 1.449 13.5 18 20.252 1.00 19.04 0.892 14.301 21.438 1.00 17.22 0.172 15.582 21.119 1.00 17.62 -0.349 16.198 22.418 1.00 15.11 -1.324 17.333 22.147 1.00 18.27 -1.550 18.177 23.353 1.00 14.34 2.139 12.244 20.757 1.00 17.36 1.728 11.151 20.397 1.00 17.98 3.136 12.351 21.587 1.00 14.79 3.861 11.169 21.974 1.00 14.85 5.296 11.312 21.506 1.00 15.82 5.439 11.262 20.008 1.00 17.24 5.187 12.380 19.192 1.00 15.15 5.340 12.297 17.802 1.00 18.45 5.834 10.084 19.402 1.00 17.80 5.986 9.997 18.025 1.00 20.12 SUBSTITIUTE SHEET (RULE CA LYS L 171 CB LYS L 171 CG LYS L 171 CD LYS L 171 CE LYS L 171 NZ LYS L 171 C LYS L 171 O LYS L 171 N TYR L 172 CA TYR L 172 CB TYR L 172 CG TYR L 172 CDI TYR L 172 GE I TYR L 172 CD2 TYR L 172 CE2 TYR L 172 WO 99/10379 WO 9910379PCT/GB98/02542 -180-

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1576 '577 '579 1580 1581 1583 1584 1585 1586 1587 1588 1589 1590 1592 1593 1594 1595 1596 1598 1599 1600 1602 1603 1604 1606 1607 1608 1610 1611 1612 1614 1615 1616 1617 1618 1619 1620 1621 1622 1624 1625 1626 1628 1629 1630 1631 1632 1633 1634 1635 1637 1638 1639 1641 1642 1643 1644 1646 1647 1648 1649 1650 1651 1652 1653 1655 1 656 165'7 1 659 1 660 1661 1 662 CZ TYR L 172 OH. TYR L 172 C TYR L 172 0 TYR L 172 N MET L 173 GA MET L 173 CB MET L 173 GG MET L 173 SD MET L 173 GE MET L 173 C MET L 173 O MET L 173 N ALA L 174 GA ALA L 174 GB ALA L 174 C ALA L 174 O ALA L 174 N SER L 175 GA SER L 175 GB SER L 175 OG SER L 175 C SER L 175 O SER L 175 N SER L 176 CA SER L 176 GB SER L 176 OG SER L 176 C SERLI176 O SER L 176 N TYR L 177 GA TYR L 177 GB TYR L 177 CG TYR L 177 GD1I TYR L 177 GElI TYR L 177 GD2 TYR L 177 GE2 TYR L 177 CZ TYR L 177 OH TYR L 177 C TYR L 177 0 TYRLI177 N LEU L 178 CA LEU L 178 GB LEU L 178 CG LEU L 178 GDI LEU L 178 GD2 LEU L 178 G LEU L 178 O LEU L 178 N THR L 179 CA THR L 179 GB THR L 179 001I THR L 179 GG2 THR L 179 C THR L 179 O THR L 179 N LEU L 180 GA LEU L 180 GB LEU L 180 G LEU L 180 CD1 LEU L 180 GD2 LEU L 180 G LEU L 180 0 LEU L 180 N THR L181 C A THR L 181 GB THR L 181 OG ITHR L 181 C G2 THR L 181 CG THR L181 O THR L 181 .N ALALI182 5.748 11.093 17.223 1.00 18.23 5.957 10.976 15.856 1.00 13.35 3.841 10.900 23.464 1.00 15.41 3.602 11.815 24.277 1.00 14.17 4.112 9.631 23.818 1.00 13.34 4.194 9.234 25.193 1.00 9.55 2.931 8.486 25.587 1.00 10.24 2.794 7.099 24.973 1.00 15.16 1.458 6.141 25.711 1.0020.11 0.057 6.915 24.983 1.00 12.86 5.456 8.378 25.432 1.00 10.38 6.004 7.765 24.500 1.00 10.40 5.930 8.343 26.659 1.00 7.39 7.129 7.587 27.004 1.00 7.66 8.390 8.338 26.542 1.00 4.47 7.156 7.374 28.522 1.00 8.50 6.346 7.968 29.237 1.00 7.42 8.060 6.527 28.988 1.00 8.85 8.159 6.230 30.403 1.00 9.69 7.271 5.021 30.757 1.00 8.09 7.689 3.814 30.105 1.00 12.41 9.605 5.954 30.779 1.00 10.11 10.411 5.525 29.919 1.00 9.58 9.977 6.234 32.047 1.00 6.07 11.314 5.932 32.491 1.00 3.46 12.184 7.164 32.459 1.00 2.00 13.552 6.858 32.672 1.00 2.00 11.231 5.316 33.891 1.00 5.39 10.250 5.490 34.564 1.00 7.78 12.225 4.527 34.231 1.00 6.76 12.241 3.756 35.441 1.00 8.12 12.040 2.273 35.114 1.00 6.07 10.666 1.876 34.571 1.00 6.17 9.606 1.588 35.440 1.00 6.94 8.349 1.237 34.936 1.00 8.14 10.422 1.793 33.200 1.00 6.52 9.168 1.445 32.703 1.00 7.03 8.134 1.170 33.568 1.00 6.45 6.868 0.863 33.077 1.00 6.11 13.563 3.877 36.093 1.00 6.87 14.572 3.831 35.422 1.00 9.13 13.555 4.030 37.390 1.00 6.48 14.757 3.989 38.155 1.00 6.11 14.992 5.304 38.851 1.00 6.46 16.223 5.442 39.717 1.00 7.03 17.486 5.050 38.981 1.00 10.30 16.302 6.871 40.214 1.00 13.82 14.621 2.881 39.154 1.00 8.35 13.684 2.853 39.899 1.00 10.42 15.562 1.969 39.137 1.00 11.56 15.533 0.803 39.975 1.00 13.47 15.700 -0.458 39.109 1.00 15.12 14.533 -0.594 38.335 1.00 14.73 15.877 -1.731 39.945 1.00 19.56 16.622 0.899 41.026 1.00 16.41 17.818 1.131 40.717 1.00 15.41 16.179 0.754 42.267 1.00 16.98 17.023 0.921 43.402 1.00 17.38 16.617 2.198 44.178 1.00 17.62 16.662 3.554 43.451 1.00 18.66 16.088 4.652 44.341 1.00 15.82 18.095 3.911 43.065 1.00 19.60 16.795 -0.231 44.3 17 1.00 15.89 15.745 -0.869 44.249 1.00 20.00 17.772 -0.505 45.141 1.00 16.39 17.568 -1.429 46.251 1.00 16.84 18.896 -1.823 46.933 1.00 15.01 19.588 -0.632 47.377 1.00 18.96 19.784 -2.619 45.988 1.00 16.62 16.757 -0.659 47.281 1.00 14.44 16.709 0.580 47.225 1.00 16.04 16.125 -1.333 48.209 1.00 15.12 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -181-

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1664 CA ALA L 182 1665 GB ALA L 182 1666 C ALA L 182 1667 0 ALA L 182 1668 N ARG L 183 1670 CA ARG L 183 1671 CB ARG L 183 1672 CG ARG L 183 1673 CD ARG L 183 1674 NE ARG L 183 1676 CZ ARG L 183 1677 NH1I ARG L 183 1680 NH2 ARG L 183 1683 C ARG L 183 1684 0 ARGL 183 1685 N ALA L 184 1687 CA ALA L 184 1688 CB ALA L 184 1689 C ALA L 184 1690 0 ALA L 184 1691 N TRP L 185 1693 CA TRP L 185 1694 CB TRP-L 185 1695 CG TRP L 185 1696 CD2 TRP L 185 1697 CE2 TRP L 185 1698 CE3 TRP L 185 1699 CDI TRP L 185 1700 NEI TRP L 185 1702 CZ2 TRP L 185 1703 CD3TRP L 185 1704 CH2 TRP L 185 1705 C TRP L 185 1706 0 TRP L 185 1707 N GLU L 186 1709 CA GLU L 186 1710 GB GLU L 186 1711 CG GLU L 186 1712 CD GLU L 186 1713 OE1 GLU L186 1714 OE2 GLU L 186 1715 C GLU L 186 1716 0 GLU L 186 1717 N ARG L 187 1719 CA ARG L 187 1720 GB ARG L 187 1721 CG ARG L 187 1722 CD ARG L 187 1723 NE ARG L 187 1725 CZ ARG L 187 1726 NH I ARG L 187 1729 NH-2 ARG L 187 1732 C ARG L 187 1733 0 ARG L 187 1734 N HIS L 188 1736 CA HIS L 188 1737 GB HIS L 188 1738 CG HIS L 188 1739 CD2 HIS L 188 1740 NDI HIS L 188 1742 GEI HIS L 188 1743 NE2 HIS L 188 1745 C HIS L 188 1746 0 HIS L 188 1747 N SER L 189 1749 CA SER L 189 1750 GB SER L 189 1751 OG SER L 189 1753 C SER L 189 1754 0 SER L 189 1755 N SER L 190 1757 CA SER L 190 15.433 -0.599 49.267 1.00 13.02 14.687 -1.565 50.182 1.00 13.78 16.448 0.264 50.092 1.00 14.39 16.130 1.387 50.509 1.00 16.28 17.676 -0.237 50.3 10 1.00 14.52 18.648 0.523 51.082 1.00 16.24 19.921 -0.291 5 1.326 1.00 19.45 21.102 0.533 51.850 1.0024.50 22.136 -0.338 52.559 1.00 29.62 23.493 0.292 52.608 1.00 35.27 24.446 -0.025 53.534 1.00 35.81 25.675 0.5 17 53.472 1.00 35.30 24.152 -0.841 54.534 1.00 36.43 18.953 1.862 50.414 1.00 18.26 18.907 2.894 51.070 1.00 19.19 19.225 1.853 49.099 1.00 16.18 19.485 3.073 48.394 1.00 10.91 19.784 2.741 46.944 1.00 9.98 18.280 4.006 48.509 1.00 12.19 18.419 5.219 48.696 1.00 11.01 17.086 3.448 48.419 1.00 10.53 15.876 4.254 48.476 1.00 11.80 14.661 3.373 48.247 1.00 11.64 13.419 4.037 48.677 1.00 9.64 12.835 5.234 48.127 1.00 14.47 11.640 5.477 48.834 1.00 14.89 13.193 6.124 47.097 1.00 14.90 12.589 3.618 49.671 1.00 15.33 11.530 4.481 49.749 1.00 15.12 10.804 6.560 48.553 1.00 15.58 12.3-68- 7.185 46.8 12 1.00 12.52 11.186 7.397 47.541 1.00 12.84 15.702 5.014 49.807 1.00 16.85 15.357 6.209 49.811 1.00 15.42 15.928 4.327 50.930 1.00 16.92 15.739 4.959 52.239 1.00 19.08 15.777 3.908 53.352 1.00 21.77 14.991 2.625 53.087 1.0025.99 15.309 1.533 54.128 0.50 26.59 16.198 1.755 54.966 0.50 23.57 14.674 0.457 54.095 0.50 23.36 16.831 5.972 52.544 1.00 20.25 16.675- 6.841 53.407 1.00 20.91 17.952 5.850 51.875 1.00 18.94 19.087 6.649 52.227 1.00 18.58 20.330 5.943 5 1.777 1.00 20.96 21.508 6.859 5 1.649 1.00 27.24 22.605 6.165 50.910 1.00 36.91 23.278 5.168 5 1.730 1.00 39.36 24.599 5.050 51.731 1.0042.54 25.192 4.147 52.498 1.00 45.47 25.330 5.841 50.948 1.00 46.06 19.054 8.072 51.679 1.00 18.28 19.749 8.944 52.205 1.00 20.00 18.277 8.324 50.623 1.00 17.48 18.250 9.671 50.014 1.00 16.15 18.574 9.596 48.475 1.00 13.42 19.894 8.957 48.210 1.00 14.37 20.268 7.652 48.233 1.00 15.01 21.083 9.664 48.217 1.00 14.95 22.132 8.871 48.278 1.00 13.98 2 1.646 7.644 48.301 1.00 15.86 16.898 10.317 50.245 1.00 16.60 15.897 9.616 50.404 1.00 18.56 16.868 11.658 50.300 1.00 18.06 15.605 12.392 50.478 1.00 17.30 15.809 13.590 51.419 1.00 20.51 16.974 14.322 51.095 1.00 18.48 15.061 12.894 49.153 1.00 18.08 13.853 12.896 48.923 1.00 21.50 15.967 13.277 48.262 1.00 17.95 15.582 13.885 46.984 1.00 17.18 SUBSTITUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -182-

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1758 1759 1761 1762 1763 1765 1766 1767 1768 1769 1770 1771 1772 1773 1775 1776 1777 1779 1780 1781 1783 1784 1785 1787 1788 1789 1790 1791 1792 1794 1795 1796 1797 1798 1799 1802 1803 1804 1806 1807 1808 1809 1810 1811 1812 1814 1815 1816 1818 1819 1820 1821 1823 1824 1825 1826 1827 1829 1830 1832 1833 1834 1836 1837 1838 1839 1840 1841 1842 1843 1844 1 846 GB SER L 190 OG SER L 190 C SER L 190 0 SER L 190 N TYR L 191 CA TYR L 191 GB TYR L 191 CG TYR L 191 CD1I TYR L 191 GEl TYR L 191 CD2 TYR L 191 CE2 TYR L 191 CZ TYR L 191 OH TYR L 191 C TYR L 191 O TYR L 191 N SERLI192 CA SER L 192 GB SER L 192 OG SERL-192 C SER L 192 0 SERLI192 N CYS L 193 CA CYS L 193 GB GYS L 193 SG CYS L 193 C CYS L 193 O GYS L 193 N GLN L 194 GA GLN L 194 CB GLN L 194 GG GLN L 194 GD GLN L 194 OEl GLN L 194 NE2 GLN L 194 C GLN L 194 O GLN L 194 N VAL L 195 CA VAL L 195 GB VAL L 195 CG1I VAL L 195 CG2 VAL L 195 C VAL L 195 O VAL L 195 N THR L 196 CA THR L 196 GB THR L 196 001I THR L 196 CG2 THR L 196 C THR L 196 O THR L 196 N HIS L 197 CA HIS L 197 GB HIS L 197 CG HIS L 197 GD2 HIS L 197 NDI HIS L 197 GEl HIS L 197 NE2 HIS L 197 C HIS L 197 0 HIS L 197 N GLU L 198 CA GLU L 198 GB GLU L 198 CG GLU L 198 GD GLU L 198 OEl GLU L 198 OE2 GLU L 198 CG GLULI198 0 GLULI198 N GLYLI199 CA GLY L 199 16.455 15.103 46.722 1.00 14.84 15.885 15.899 45.705 1.00 24.95 15.694 12.933 45.8 10 1.00 15.72 16.732 12.295 45.605 1.00 16.39 14.628 12.850 45.058 1.00 15.74 14.620 12.066 43.811 1.00 18.47 13.883 10.737 44.028 1.00 20.26 14.571 9.846 45.036 1.00 20.87 15.609 9.0 14 44.623 1.00 23.39 16.310 8.223 45.512 1.00 22.95 14.227 9.864 46.412 1.00 24.18 14.929 9.066 47.317 1.00 26.25 15.986 8.247 46.847 1.00 26.73 16.779 7.529 47.725 1.00 30.08 13.935 12.894 42.700 1.00 17.55 12.932 13.528 42.950 1.00 14.74 14.465 12.884 41.473 1.00 16.33 13.898 13.735 40.454 1.00 15.90 14.701 15.039 40.443 1.00 18.03 14.126 15.961 39.550 1.00 23.10 13.953 13.134 39.074 1.00 12.29 14.990 12.656 38.672 1.00 14.68 12.855 13.191 38.355 1.00 11.59 12.853 12.802 36.945 1.00 14.23 11.629 11.969 36.620 1.00 15.78 11.551 11.355 34.910 1.00 15.09 12.850 14.061 36.089 1.00 12.46 11.931 14.841 36.189 1.00 14.42 13.866 14.264 35.249 1.00 14.04 13.938 15.495 34.451 1.00 14.30 15.219 16.234 34.720 1.00 20.47 15.534 16.382 36.170 1.00 26.89 16.720 17.269 36.375 1.00 33.09 16.900 17.827 37.468 1.00 36.67 17.551 17.413 35.332 1.00 36.22 13.882 15.206 32.984 1.00 13.96 14.743 14.534 32.463 1.00 11.43 12.885 15.763 32.339 1.00 13.39 12.624 15.500 30.942 1.00 15.15 11.177 15.057 30.783 1.00 13.26 10.871 14.802 29.321 1.00 12.28 10.912 13.829 31.659 1.00 8.74 12.836 16.749 30.071 1.00 16.35 12.025 17.685 30.106 1.00 15.34 13.925 16.755 29.301 1.00 16.92 14.195 17.864 28.382 1.00 15.93 15.708 18.008 28.168 1.00 18.12 16.349 18.212 29.431 1.00 22.55 16.022 19.183 27.264 1.00 21.24 13.507 17.634 27.035 1.00 16.18 13.738 16.581 26.401 1.00 14.99 12.654 18.626 26.614 1.00 14.43 11.933 18.569 25.350 1.00 13.60 10.444 18.344 25.574 1.00 12.56 9.598 18.345 24.318 1.00 9.47 9.559 17.496 23.283 1.00 8.75 8.524 19.223 24.096 1.00 13.69 7.874 18.920 22.993 1.00 10.65 8.493 17.880 22.507 1.00 13.24 12.079 19.889 24.609 1.00 19.15 11.361 20.879 24.932 1.0021.46 12.904 19.875 23.571 1.00 19.88 13.178 21.067 22.771 1.00 23.30 11.897 21.658 22.160 1.00 25.45 11.074 20.703 21.325 1.00 25.96 11.437 20.714 19.863 1.00 29.67 12.403 20.003 19.479 1.00 31.64 10.744 21.423 19.089 1.00 27.15 13.840 22.126 23.632 1.00 25.19 13.378 23.250 23.683 1.00 25.37 14.874 21.736 24.360 1.00 26.71 15.647 22.699 25.107 1.0028.67 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -183-

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1847 1848 1849 1851 1852 1853 1854 1855 1857 1858 1860 1861 1862 1864 1865 1866 1868 1869 1870 1871 1873 1874 1875 1876 1877 1878 1879 1881 1882 1883 1884 1885 1886 1887 1888 1889 1891 1892 1893 1894 1895 1896 1900 1901 1902 1904 1905 1906 1908 1909 1910 1912 1913 1914 1915 1916 1917 1918 1919 1921 1922 1923 1 925 1 926 1 927 1 92S 193( 1931 1 93' 1933 1 93~ 193 C GLY L 199 GLY L 199 N HIS L200 CA HIS L200 CB HIS L200 CG HIS L200 CD2 HIS L 200 ND I HIS L 200 GElI HIS L 200 NE2 HIS L 200 C HIS L200 O HIS L200 N THRL 201 CA THR L201 CB THR L201 OG I THRL 201 GG2 THR L 201 C THR L201 O THR L201 N VALL 202 CA VAL L 202 GB3 VAL L 202 CG I VAL L202 CG2 VAL L 202 C VAL L202 O VAL L202 N GLU L203 CA GLU L203 GB3 GLUL 203 CG GLU L203 CD GLUL 203 OE1I GLU L203 0E2 GLU L 203 C GLU L203 0 GLUL 203 N LYSL 204 CA LYSL 204 GB3 LYSL 204 CG LYSL 204 CD LYSL 204 CE LYSL 204 NZ LYS L 204 C LYS L204 O LYSL 204 N SER L205 CA SER L 205 GB3 SER L 205 OG SER L 205 C SER L205 O SERL 205 N LEU L206 CA LEU L 206 GB LEU L 206 CG LEU L206 CD1I LEUL 206 CD2 LEU L 206 C LEUL 206 0 LEUL 206 N SERL 207 CA SERL 207 GB3 SER L207 OG SERL 207 C SER L207 O SER L207 !N ARGL 208 CA ARG L208 GB3 ARGL 208 C G ARGL 208 CD ARG L208 INE ARG L208 S CZ ARGL 208 5 NHI ARG L20 15.025 23.177 26.398 1.00 30.20 15.631 24.007 27.078 1.00 31.36 13.821 22.685 26.738 1.00 29.31 13.164 23.095 27.979 1.00 29.70 11.788 23.748 27.741 1.00 34.13 11.606 24.407 26.407 1.0042.18 12.497 24.946 25.537 1.00 44.52 10.379 24.476 25.758 1.00 45.60 10.501 25.004 24.543 1.00 46.26 11.777 25.293 24.405 1.00 46.19 12.959 21.876 28.832 1.00 27.60 12.335 20.909 28.372 1.00 27.65 13.458 21.932 30.064 1.00 27.03 13.375 20.797 30.979 1.00 25.96 14.629 20.751 31.867 1.00 22.54 15.756 20.698 31.036 1.00 21.22 14.670 19.519 32.748 1.00 22.94 12.109 20.851 31.845 1.00 26.78 11.855 2 1.863 32.498 1.00 29.53 11.274 19.784 31.774 1.0025.81 10.113 19.636 32.674 1.00 22.79 8.877 19.139 31.905 1.0024.16 7.656 19.088 32.826 1.00 24.52 8.621 20.060 30.717 1.00 24.14 10.492 18.614 33.772 1.00 21.74 10.951 17.538 33.472 1.00 19.01 10.315 18.949 35.044 1.00 20.40 10.780 18.077 36.078 1.00 19.67 12.018 18.713 36.708 1.00 22.14 12.565 17.936 37.876 1.00 27.78 13.321 18.815 38.856 0.50 30.15 14.570 18.902 38.736 0.50 30.52 12.662 19.418 39.748 0.50 30.93 9.736 17.757 37.155 1.00 18.69 8.856 18.556 37.465 1.00 19.41 9.810 16.552 37.676 1.00 16.36 9.052 16.197 38.843 1.00 14.59 7.969 15.235 38.542 1.00 15.55 6.861 15.888 37.769 1.00 21.54 6.406 17.133 38.481 1.00 21.69 5.275 17.775 37.720 1.00 22.39 4.051 16.981 37.871 1.00 20.85 9.994 15.617 39.854 1.00 15.55 11.022 14.984 39.499 1.00 13.34 9.673 15.854 41.125 1.00 17.28 10.536 15.433 42.199 1.00 16.96 11.321 16.626 42.766 1.00 18.69 12.422 16.990 41.919 1.00 25.46 9.743 14.825 43.299 1.00 16.29 8.584 15.118 43.445 1.00 12.40 10.409 13.959 44.032 1.00 17.28 9.869 13.340 45.223 1.00 20.60 9.926 11.804 45.106 1.00 18.66 9.060 11.155 44.021 1.00 17.51 9.529 9.738 43.756 1.00 19.23 7.587 11.167 44.424 1.00 16.04 10.748 13.756 46.392 1.00 22.29 11.966 13.806 46.263 1.00 20.72 10.137 14.114 47.488 1.00 26.92 10.898 14.334 48.709 1.00 33.08 10.508 15.631 49.412 1.00 32.95 11.284 15.814 50.584 1.00 35.61 10.580 13.160 49.618 1.00 35.86 9.401 12.806 49.798 1.00 38.31 11.603 12.538 50.143 1.0036.32 11.421 11.382 50.977 1.00 36.19 12.244 10.211 50.365 1.00 33.25 11.945 8.857 50.961 1.0031.97 13.215 8.117 51.322 1.0032.82 13.075 7.3 14 52.547 1.00 37.28 13.873 7.494 53.619 1.0043.16 8 13.749 6.729 54.723 1.00 43.30 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -184-

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1939 1942 1943 1944 1945 1946 1947 1950 1952 1953 1955 1956 1957 1958 1959 1960 1961 1963 1964 1965 1966 1967 1968 1971 1972 1973 1975 1976 1977 1978 1979 1980 1981 1982 1984 1985 1986 1987 1988 1989 1992 1993 1994 1996 1997 1998 1999 2000 2001 2002 2003 2004 2006 2007 2008 2010 2011 2012 2014 2015 2016 2017 2019 2020 2021 2022 2024 2025 2026 2027 2029 2030 NH2 ARG L 208 C ARG L 208 OTI ARG L 208 OT2 ARG L 208 CB ALA H I C ALA H I O ALAH I N ALA H I CA ALA H I N VALH 2 CA VAL H 2 CB VAL H 2 CGIVALH 2 CG2 VAL H 2 C VALH 2 O VALH 2 N GLNH 3 CA GLN H 3 CB GLN H 3 CG GLN H 3 CD GLN H 3 OEI GLNH 3 NE2 GLN H 3 C GLN H 3 o GLNH 3 N LEU H 4 CA LEU H 4 CB LEU H 4 CG LEU H 4 CDI LEUH 4 CD2 LEU H 4 C LEUH 4 O LEU H 4 N GLNH 5 CA GLN H 5 CB GLN H 5 CG GLN H 5 CD GLN H 5 OE1GLNH 5 NE2 GLN H 5 C GLNH 5 O GLNH 5 N GLUH 6 CA GLU H 6 CB GLU H 6 CG GLU H 6 CD GLU H 6 OEI GLU H 6 OE2 GLU H 6 C GLU H 6 O GLU H 6 N SERH 7 CA SER H 7 CB SERH 7 OG SERH 7 C SERH 7 O SERH 7 N GLY H 8 CA GLY H 8 C GLY H 8 O GLYH 8 N GLYH 9 CA GLY H 9 C GLY H 9 O GLY H 9 N GLYH 10 CA GLY H 10 C GLYH 10 O GLYH 10 N LEUH 11 CA LEU H II CB LEU H 11 14.794 8.460 53.596 1.00 45.46 11.855 11.788 52.407 1.00 37.35 12.824 11.196 52.969 1.00 38.30 11.246 12.774 52.926 1.00 37.56 -0.771 -4.993 -4.626 1.00 35.02 1.178 -6.505 -4.919 1.00 32.62 0.788 -7.588 -4.494 1.00 32.59 -0.545 -6.367 -6.682 1.00 37.70 0.204 -5.591 -5.634 1.00 34.79 2.429 -6.057 -4.804 1.00 29.87 3.463 -6.831 -4.147 1.00 28.68 4.806 -6.124 -4.242 1.00 27.24 5.892 -6.933 -3.552 1.00 30.14 5.136 -5.894 -5.708 1.00 30.41 3.135 -7.053 -2.694 1.00 27.59 2.532 -6.207 -2.034 1.00 27.26 3.506 -8.200 -2.213 1.00 25.47 3.315 -8.504 -0.833 1.00 24.24 1.885 -9.027 -0.578 1.00 26.56 1.609 -9.380 0.905 1.00 33.26 0.370-10.261 1.157 1.00 38.06 0.094-11.216 0.415 1.00 40.20 -0.369 -9.958 2.240 1.00 38.60 4.334 -9.535 -0.380 1.00 21.45 4.464 -10.584 -0.995 1.00 22.59 5.099 -9.192 0.641 1.00 19.37 5.998-10.150 1.300 1.00 16.61 7.394 -9.545 1.486 1.00 13.50 8.174 -9.232 0.194 1.00 8.19 9.510 -8.607 0.523 1.00 3.80 8.394 -10.506 -0.603 1.00 8.33 5.388 -10.500 2.669 1.00 15.88 4.960 -9.611 3.396 1.00 15.82 5.324-11.767 3.017 1.00 14.17 4.655 -12.155 4.267 1.00 15.42 3.283 -12.680 3.908 1.00 16.35 2.311 -12.925 5.035 1.00 22.48 1.003 -13.532 4.494 1.00 29.57 0.366-14.355 5.154 1.00 35.66 0.593 -13.150 3.278 1.00 31.58 5.470 -13.205 5.002 1.00 13.97 5.590 -14.349 4.539 1.00 9.52 6.059-12.801 6.131 1.00 13.08 6.917 -13.705 6.900 1.00 9.47 7.848 -12.956 7.823 1.00 9.95 8.813-12.021 7.131 1.00 9.95 8.237 -10.662 6.799 1.00 5.17 9.055 -9.778 6.461 1.00 8.80 6.983 -10.462 6.843 1.00 4.90 6.088 -14.632 7.736 1.00 12.71 4.884-14.408 7.914 1.00 13.94 6.742 -15.650 8.270 1.00 13.48 6.095 -16.642 9.106 1.00 13.96 5.381 -17.653 8.220 1.00 15.10 4.049-17.289 8.102 1.0023.26 7.104-17.404 9.919 1.00 12.29 8.268 -17.411 9.591 1.00 13.84 6.622 -18.093 10.961 1.00 12.53 7.462 -19.033 11.663 1.00 10.51 8.096-18.494 12.907 1.00 12.14 8.763 -19.233 13.581 1.00 16.56 7.903 -17.217 13.236 1.00 10.59 8.527 -16.709 14.450 1.00 14.05 7.920-17.295 15.753 1.00 16.57 6.760 -17.800 15.770 1.00 17.72 8.667 -17.200 16.843 1.00 16.58 8.149-17.666 18.129 1.00 15.33 9.140 -17.445 19.220 1.00 12.28 10.150-16.758 19.006 1.00 11.60 8.841 -18.042 20.383 1.00 13.95 9.706 -17.995 21.590 1.00 14.48 8.814-18.096 22.825 1.00 14.29 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -185-

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203 1 2032 2033 2034 2035 2036 2038 2039 2040 2041 2042 2043 2044 2046 2047 2048 2049 2050 2051 2054 2055 2056 2057 2058 2059 2060 2061 2062 2063 2065 2066 2067 2068 2070 2071 2072 2073 2075 2076 2077 2079 2080 2081 2083 2084 2085 2086 2087 2088 2089 2090 2092 2093 2094 2095 2096 2097 2101 2102 2103 2105 21 06 21 07 21 08 21 0S 211( 2111 2111 211' 211I 21 1 2111 CG LEU H 11I CD] LEU H I I CD2 LEU H I I C LEUH 11 o LEUH 11 N VAL H 12 CA VALI-H 12 CB VAL H 12 CG IVAL H 12 CG2 VAL H 12 C VAL H 12 O VAL H 12 N GLN H 13 CA GLN H 13 CB GLN H 13 CG GLN H 13 CD GLN H 13 OEI GLN H 13 NE2 GLN H 13 C GLN H 13 GLN H 13 N PRO H 14 CD PRO H 14 CA PRO H 14 CB PRO H 14 CG PRO H 14 C PRO H 14 O PRO H 14 N GLY H 15 CA GLY H 15 C GLY H 15 O GLY H 15 N GLY H 16 CA GLYI- 16 C GLYI-H 16 O GLY H 16 N SER H 17 CA SER H 17 CB SER H 17 OG SER H 17 C SER H 17 O SER H 17 N MET H 18 CA MET H 18 CB MET H 18 CG MET H 18 SD MET H 18 CE MET H 18 C MET H 18 0 MET H 18 N LYS H 19 CA LYS H 19 CB LYS H 19 CG LYS H 19 CD LYS H 19 CE LYS H 19 NZ LYS H 19 C LYS H 19 *0 LYS H 19 N LEUH 20 CA LEU H 20 CB LEU H 20 CG LEU H 20 CD I LEU H 20 CD2 LEU H 20 )C LEUH 20 I0 LEU H 20 N SER H 21 t CA SER H 21 5 CB SER H 21 6 OG SER H 21 8 C SERH 21 9.200 -17.433 24.155 1.00 13.64 8.420 -18.169 25.235 1.00 13.85 10.696 -17.445 24.479 1.00 4.07 10.586 -19.229 21.577 1.00 14.46 10.096 -20.290 2 1.346 1.00 15.77 11.855-_19.096 21.901 1.00 18.00 12.774 -20.220 2 1.888 1.00 15.52 13.455 -20.297 20.469 1.00 18.43 14.970 -20.237 20.592 1.00 13.84 13.024 -21.558 19.726 1.00 16.77 13.832 -20.013 22.992 1.00 15.38 14.172 -18.875 23.352 1.00 13.69 14.355 -21.090 23.558 1.00 16.57 15.372 -20.934 24.580 1.00 15.98 15.310 -22.083 25.580 1.00 19.24 14.104 -22.074 26.537 1.00 26.05 14.446 -22.629 27.939 1.00 28.25 15.429 -23.367 28.124 1.0031.14 13.645 -22.259 28.945 1.00 33.04 16.729 -20.924 23.920 1.00 14.00 16.870 -2 1.344 22.773 1.00 15.42 17.722 -20.356 24.540 1.00 12.23 17.659 -19.512 25.729 1.00 12.38 19.046 -20.372 23.965 1.00 12.75 19.907 -19.769 25.057 1.00 10.09 18.951 -18.757 25.601 1.00 13.06 19.398 -21.817 23.621 1.00 14.12 19.080 -22.734 24.394 1.00 16.21 20.019 -22.013 22.451 1.00 10.07 20.300 -23.355-21.945 1.00 7.80 19.221 -23.789 20.965 1.00 5.91 19.394 -24.744 20.198 1.00 6.43 18.137 -23.048 20.952 1.00 2.35 17.015 -23.406 20.134 1.00 6.43 17.260 -23.284 18.627 1.00 6.38 18.264 -22.765 18.168 1.00 6.92 16.262 -23.672 17.887 1.00 12.18 16.323 -23.705 16.436 1.00 11.41 16.774 -25.123 16.079 1.00 15.73 16.883 -25.332 14.702 1.00 22.31 14.909 -23.414 15.882 1.00 12.78 13.930 -23.826 16.500 1.00 16.32 14.783 -22.667 14.769 1.00 8.79 13.488 -22.464 14.117 1.00 10.28 12.565 -21.433 14.815 1.00 13.63 13.176 -20.133 15.324 1.00 16.88 11.965 -19.096 16.237 1.00 27.06 10.504 -20.163 16.269 1.00 3.15 13.665 -22.059 12.668 1.00 9.07 14.738 -21.626 12.254 1.00 10.49 12.612 -22.185 11.907 1.00 10.93 12.675 -21.815 10.531 1.00 11.83 12.600 -23.056 9.625 1.00 14.90 12.550 -22.773 8.094 1.00 17.52 13.043 -23.984 7.299 1.00 20.23 12.526 -24.038 5.865 1.00 19.51 11.280 -24.851 5.769 1.00 22.58 11.572 -20.843 10.207 1.00 13.18 10.395 -21.073 10.502 1.00 12.84 11.995 -19.731 9.610 1.00 12.76 11.094 -18.710 9.160 1.00 9.79 11.700 -17.326 9.443 1.00 11.85 12.231 -17.080 10.874 1.00 9.81 12.775 -15.658 10.967 1.00 4.16 11.135 -17.333 11.908 1.00 4.65 10.855 -18.856 7.673 1.00 9.78 11.714 -19.325 6.922 1.00 8.56 9.699 -18.478 7.281 1.00 9.36 9.317 -18.520 5.911 1.00 13.01 8.269 -19.586 5.707 1.00 14.00 8.803 -20.857 5.993 1.00 19.15 8.764 -17.193 5.469 1.00 13.78 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -186-

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2119 2120 2122 2123 2124 2125 2126 2127 2129 2130 2131 2132 2133 2134 2135 2137 2138 2139 2140 2141 2143 2144 2145 2147 2148 2149 2151 2152 2153 2154 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2168 2169 2170 2172 2173 2174 2175 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2189 2190 2191 2193 2194 2195 2197 2198 2199 2200 2201 2204 2205 O SER H 21 N CYS H 22 CA CYS H 22 CB CYS H 22 SG CYS H 22 C CYS H 22 O CYS H 22 N VAL H 23 CA VAL H 23 CB VAL H 23 CGI VAL H 23 CG2 VAL H 23 C VAL H 23 O VAL H 23 N ALA H 24 CA ALA H 24 CB ALA H 24 C ALA H 24 O ALA H 24 N SERH 25 CA SER H 25 CB SER H 25 OG SER H 25 C SER H 25 O SER H 25 N GLY H 26 CA GLY H 26 C GLY H 26 O GLY H 26 N PHE H 27 CA PHEH 27 CB PHE H 27 CG PHE H 27 CD1 PHEH 27 CD2 PHE H 27 CEl PHE H 27 CE2 PHE H 27 CZ PHE H 27 C PHE H 27 O PHE H 27 N THR H 28 CA THRH 28 CB THRH 28 OGI THRH 28 CG2 THR H 28 C THRH 28 O THRH 28 N PHE H 29 CA PHE H 29 CB PHE H 29 CG PHE H 29 CD1 PHE H 29 CD2 PHE H 29 CEI PHEH 29 CE2 PHE H 29 CZ PHE H 29 C PHE H 29 O PHE H 29 N SER H 30 CA SERH 30 CB SER H 30 OG SERH 30 C SER H 30 O SER H 30 N ASN H 31 CA ASN H 31 CB ASN H 31 CG ASN H 31 ODI ASN H 31 ND2 ASN H 31 C ASNH 31 O ASN H 31 8.160-16.471 6.260 1.00 18.18 9.003 -16.860 4.194 1.00 16.70 8.497-15.627 3.596 1.00 13.01 9.603 -14.560 3.511 1.00 11.58 9.160-13.148 2.429 1.00 13.80 7.993-15.912 2.193 1.0011.47 8.708 -16.423 1.375 1.00 13.22 6.768-15.578 1.938 1.00 14.16 6.184-15.802 0.639 1.00 16.31 4.857-16.604 0.748 1.00 17.85 5.151-17.911 1.457 1.0021.18 3.799-15.822 1.518 1.00 19.36 5.922 -14.476 -0.023 1.00 16.44 5.303 -13.570 0.574 1.00 12.06 6.400-14.380 -1.263 1.00 19.48 6.275 -13.152 -2.068 1.00 19.91 7.604 -12.884 -2.748 1.00 18.96 5.182 -13.278 -3.117 1.00 21.31 4.953 -14.374 -3.667 1.00 24.23 4.500-12.194 -3.409 1.00 19.69 3.488 -12.248 -4.429 1.00 20.48 2.159-12.558 -3.789 1.00 19.79 1.875 -11.574 -2.821 1.00 22.03 3.390 -10.925 -5.133 1.00 20.75 3.863 -9.909 -4.618 1.00 20.32 2.746 -10.932 -6.294 1.00 22.48 2.508 -9.680 -7.010 1.00 24.12 3.713 -9.139 -7.796 1.00 25.02 3.709 -7.955 -8.176 1.00 22*99 4.728 -10.018 -8.013 1.00 24.04 5.932 -9.707 -8.790 1.00 22.13 6.819 -8.649 -8.091 1.00 23.23 7.740 -9.173 -6.996 1.0020.65 9.114 -9.356 -7.245 1.00 19.81 7.255 -9.425 -5.712 1.00 19.64 9.970 -9.775 -6.231 1.00 18.67 8.117 -9.832 -4.703 1.00 16.42 9.464 -10.010 -4.959 1.00 16.29 6.736 -10.993 -9.003 1.00 22.10 6.519 -12.007 -8.308 1.00 25.47 7.689 -10.939 -9.919 1.00 17.46 8.483 -12.084 -10.233 1.00 16.95 9.046 -1 1.951 -11.625 1.00 18.84 7.939 -11.733 -12.511 1.00 19.87 9.793 -13.214 -12.017 1.00 17.78 9.594 -12.306 -9.258 1.00 16.32 10.757 -11.907 -9.499 1.00 13.29 9.237-13.013 -8.176 1.00 17.39 10.185 -13.319 -7.092 1.00 12.65 9.520 -14.291 -6.099 1.00 14.38 10.415-14.836 -5.010 1.00 13.29 10.570 -14.135 -3.802 1.00 17.17 11.067 -16.058 -5.159 1.00 11.79 11.370 -14.654 -2.765 1.00 16.24 11.864-16.586 -4.138 1.00 8.50 12.022 -15.887 -2.946 1.00 14.16 11.482 -13.895 -7.605 1.00 11.31 12.555-13.533 -7.112 1.00 11.15 11.385 -14.789 -8.631 1.00 10.88 12.565-15.474 -9.210 1.00 10.24 12.113-16.379-10.389 1.00 10.59 10.698 -16.481 -10.425 1.00 20.09 13.661 -14.529 -9.727 1.00 8.21 14.839 -14.924 -9.823 1.00 6.56 13.257-13.299-10.109 1.00 10.86 14.172 -12.323 -10.737 1.00 10.45 13.378 -11.306 -11.569 1.00 13.88 12.865 -11.830 -12.887 1.00 17.90 13.200 -12.948 -13.307 1.00 17.77 12.035 -11.023 -13.549 1.00 20.48 15.033 -11.520 -9.762 1.00 11.11 15.987 -10.848 -10.199 1.00 11.57 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -187-

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2206 2208 2209 2210 2211 2212 2213 2214 2215 2216 2218 2219 2220 2222 2223 2224 2225 2226 2227 2228 2229 2231 2232 2233 2234 2235 2236 2238 2239 2240 2241 2242 2243 2244 2245 2247 2248 2249 2250 2251 2254 2255 2256 2258 2259 2260 2261 2262 2263 2264 2265 2267 2268 2269 2270 2271 2272 2274 2275 2276 2277 2278 2279 2280 2282 2283 22841 2285 2286 2288 228S 229: N TYR H32 CA TYR H 32 CB TYR H 32 CG TYR H 32 CDI TYR H 32 CEI TYR H 32 GD2 TYR H 32 GE2 TYR H 32 CZ TYR H 32 OH TYR H 32 C TYR H 32 0 TYR H 32 N TRP H33 CA TRP H 33 CB TRP H 33 CG TRP H 33 CD2 TRP H 33 CE2 TRP H 33 CE3 TRP H 33 CDI TRP H 33 NEI1TRP H 33 CZ2 TRP H 33 CD3 TRP H- 33 CH2 TRP H 33 C TRP H33 0 TRP H33 N MET H34 CA MET H 34 GB MET H 34 CG MET H 34 SD MET H 34 CE MET H 34 C MET H34 0 MET H 34 N ASNH 35 CA ASN H 35 GB ASN H 35 CG ASN H 35 OD1 ASN H 35 ND2 ASN H 35 C ASN H35 0 ASNH 35 N TRP H 36 CA TRP H 36 GB TRP H 36 CG TRP H 36 CD2 TRP H 36 CE2 TRP H 36 CE3 TRP H 36 CDI TRP H 36 NEI1TRP H 36 CZ2 TRP H 36 CZ3 TRP H 36 CH2 TRP H 36 C TRP H 36 0 TRP H 36 N VAL H37 CA VAL H 37 GB VAL H 37 CG IVAL H 37 GG2 VAL H 37 C VAL H 37 0 VAL H 37 N ARG H38 CA ARG H 38 GB ARG H 38 CG ARG H 38 GD ARG H 38 NE ARG H 38 GZ ARG H 38 NH1 ARG H 38 NH2 ARG H 38 14.689 -11.518 -8.473 1.00 10.42 15.459 -10.727 -7.512 1.00 7.72 14.575 -9.640 -6.921 1.00 10.35 13.995 -8.726 -7.958 1.00 10.12 12.717 -8.975 -8.451 1.00 11.35 12.192 -8.238 -9.513 1.00 13.96 14.752 -7.703 -8.543 1.00 10.05 14.232 -6.947 -9.624 1.00 10.42 12.948 _7.222 -10.096 1.00 13.65 12.367 -6.454 -11.099 1.00 13.93 16.069 -11.541 -6.376 1.00 8.75 15.564 -12.610 -5.991 1.00 8.92 17.176 -11.022 -5.853 1.00 7.78 17.752 -11.580 -4.698 1.00 6.34 19.106 -10.961 -4.343 1.00 3.32 20.136-_10.905 -5.409 1.00 5.31 21.486-10.435 -5.224 1.00 2.32 22.122 -10.485 -6.481 1.00 3.83 22.204 -9.973 -4.111 1.00 5.74 19.998 -11.225 -6.740 1.00 2.00 21.192 -10.969 -7.368 1.00 3.99 23.432 -10.079 -6.667 1.00 5.36 23.509 -9.569 -4.289 1.00 8.48 24.108 -9.621 -5.564 1.00 7.99 16.815 -11.212 -3.551 1.00 8.26 16.037 -10.228 -3.655 1.00 6.24 16.909 -11.993 -2.473 1.00 7.22 16.136 -11.747 -1.260 1.00 8.81 15.113 -12.849 -1.097 1.00 7.01 13.926 -12.741 -2.048 1.00 10.07 12.892 -11.274 -1.831 1.00 17.49 11.950 -11.773 -0.390 1.00 17.44 17.089 -11.678 -0.049 1.00 7.51 18.193 -12.255 -0.093 1.00 10.32 16.724 -10.902 0.988 1.00 6.44 17.570 -10.757 2.181 1.00 4.54 18.186 -9.341 2.317 1.00 5.78 18.891 -8.806 1.076 1.00 3.57 20.129 -8.691 1.016 1.00 2.44 18.102 -8.488 0.098 1.00 2.00 16.725 -10.942 3.442 1.00 4.23 15.486 -1t0.826 3.400 1.00 2.00 17.398 -11.276 4.537 1.00 4.82 16.746 -11.240 5.834 1.00 6.51 16.864 -12.558 6.601 1.00 4.15 15.872 -13.568 6.103 1.00 6.17 14.487 -13.756 6.501 1.00 5.59 13.954 -14.755 5.666 1.00 7.68 13.621 -13.187 7.474 1.00 3.55 16.100 -14.433 5.087 1.00 7.43 14.963 -15.123 4.843 1.00 11.31 12.625 -15.216 5.745 1.00 7.42 12.274 -13.649 7.551 1.00 2.61 11.798 -14.642 6.698 1.00 5.75 17.375 -10.107 6.625 1.00 3.69 18.599 -9.923 6.618 1.00 3.88 16.546 -9.299 7.239 1.00 8.04 17.063 -8.196 8.049 1.00 4.88 16.851 -6.839 7.327 1.00 7.93 17.141 -5.666 8.291 1.00 5.70 17.755 -6.752 6.084 1.00 4.88 16.264 -8.195 9.353 1.00 7.96 15.041 -8.274 9.288 1.00 10.89 16.920 -8.092 10.498 1.00 4.79 16.179 -8.134 11.783 1.00 6.19 16.710 -9.288 12.699 1.00 2.00 18.086 -9.070 13.392 1.00 5.85 18.656 -10.358 14.059 1.00 7.03 20.110 -10.251 14.276 1.00 5.02 20.873 -11.259 14.656 1.00 7.94 22.155 -11.056 14.911 1.00 8.02 20.371 -12.477 14.749 1.00 10.78 SUBSTITUT SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -188-

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2295 2296 2297 2299 2300 2301 2302 2303 2304 2307 2308 2309 231 1 2312 2313 2315 2316 2317 2318 2319 2320 2321 2322 2323 2324 2326 2327 2328 2329 2330 2332 2333 2334 2335 2336 2337 2341 2342 2343 2345 2346 2347 2348 2350 2351 2352 2353 2354 2355 2356 2357 2359 2360 2361 2362 2363 2364 2365 2366 2367 2369 2370 2371 2372 2373 2374 2375 2376 2378 2379 2380 2381 C ARG H138 0 ARG H38 N GLN H39 CA GLN H 39 CB3 GLN H 39 CG GLN H 39 CD GLN H 39 OE1 GLN H 39 NE2 GLN H 39 C GLN H 39 0 GLN H39 N SERH 40 CA SER H 40 GB SER H 40 OG SER H 40 C SERH 40 0 SER H40 N PRO H41 CD PRO H 41 CA PRO H 41 GB3 PRO H 41 CG PRO H 41 C PROH 41 0 PRO H41 N ALA H42 CA ALA H 42 CB3 ALA H 42 C ALA H42 O ALA H42 N LYS H43 CA LYS H 43 CB LYS H 43 CG LYS H 43 CD LYS H 43 CE. LYS H 43 NZ LYS H 43 C LYS H43 0 LYS H43 N GLY H44 CA GLY H 44 C GLY H44 0 GLY H44 N LEU H45 CA LEU H 45 GB3 LEU H 45 CG LEU H 45 CDI LEU H 45 CD2 LEU H 45 C LEU H45 O LEU H45 N GLU H46 CA GLU H 46 C1B GLU H 46 CG GLU H 46 CD GLU H 46 OE1 GLU H 46 OE2 GLU H 46 C GLU H46 O GLU H46 N TRP H47 CA TRP H 47 GB TRP H 47 CG TRP H 47 CD2 TRP H 47 CE2 TRP H 47 CE3 TRP H 47 CD1 TRP H 47 NEI TRP H 47 CZ2 TRP H 47 CD TRP H 47 CH2 TRP H 47 C TRP H47 16.218 -6.778 12.557 1.00 9.00 17.166 -5.974 12.456 1.00 7.20 15.192 -6.533 13.332 1.00 10.07 15.154 -5.306 14.106 1.00 13.88 13.927 -4.499 13.692 1.00 12.70 13.871 -3.134 14.351I 1.00 13.88 12.577 -2.435 14.096 1.00 10.90 11.578 -3.045 13.669 1.00 14.02 12.570 -1.148 14.354 1.00 19.33 15.104 -5.631I 15.638 1.00 17.21 14.152 -6.292 16.096 1.00 11.06 16.149 -5.178 16.387 1.00 20.54 16.224 -5.375 17.840 1.00 25.32 17.438 -6.241 18.210 1.00 24.24 18.604 -5.445 18.333 1.00 26.93 16.372 -4.024 18.534 1.00 26.35 17.020 -3.133 17.987 1.00 27.60 15.807 -3.856 19.773 1.00 29.80 15.073 -4.886 20.544 0.50 26.67 15.898 -2.583 20.548 1.00 29.86 15.219 -2.942 21.868 0.5028.55 15.354 -4.430 21.937 0.5027.83 17.364 -2.097 20.737 1.00 33.07 17.739 -0.945 20.398 1.00 33.27 18.195 -3.003 21.209 1.0034.06 19.604 -2.687 21.463 1.00 37.51 20.217 -3.817 22.304 1.00 37.30 20.448 -2.486 20.178 1.00 37.45 21.615 -2.062 20.265 1.00 38.47 19.875 -2.769 18.997 1.00 36.93 20.689 -2.786 17.797 1.0035.11 21.042 -4.231 17.444 1.00 36.81 21.939 -4.939 18.459 1.0040.66 22.518 -6.260 17.908 1.0040.17 21.551 -7.452 18.065 1.0038.65 22.189 -8.748 17.670 1.00 34.06 20.078 -2.132 16.570 1.00 32.32 20.735 -2.094 15.541 1.00 32.74 18.867 -1.613 16.648 1.00 28.07 18.254 -1.086 15.428 1.00 26.41 18.243 -2.166 14.329 1.00 22.61 18.060 -3.372 14.656 1.0021.36 18.487 -1.765 13.052 1.00 18.78 18.452 -2.735 11.913 1.00 14.74 18.017 -2.075 10.586 1.00 10.90 16.517 -1.769 10.423 1.00 7.35 16.263 -1.084 9.109 1.00 8.68 15.661 -3.020 10.517 1.00 4.89 19.768 -3.456 11.710 1.00 13.85 20.871 -2.869 11.727 1.00 11.97 19.674 -4.761 11.517 1.00 13.05 20.873 -5.546 11.302 1.00 10.92 21.260 -6.307 12.583 1.00 12.86 22.733 -6.645 12.659 1.00 21.14 23.067 -7.738 13.653 1.00 24.52 22.400 -7.816 14.716 1.00 28.63 24.015 -8.510 13.375 1.00 25.36 20.648 -6.540 10.150 1.00 9.90 19.726 -7.366 10.196 1.00 6.95 21.476 -6.428 9.123 1.00 7.54 21.355 -7.311 7.982 1.00 7.90 22.064 -6.701 6.740 1.00 10.76 22.169 -7.636 5.565 1.00 5.45 23.313 -8.463 5.242 1.00 3.79 23.012 -9.172 4.083 1.00 2.00 24.572 -8.670 5.845 1.00 3.96 21.210 -7.873 4.602 1.00 4.22 21.740 -8.799 3.718 1.00 5.25 23.9 13 -10.066 3.502 1.00 2.56 25.451 -9.562 5.268 1.00 2.00 25.116-10.235 4.110 1.00 2.00 21.937 -8.650 8.367 1.00 2.55 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -189-

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2382 2383 2385 2386 2387 2388 2389 2390 2391 2393 2394 2395 2396 2397 2399 2400 2401 2402 2403 2404 2405 2406 2407 2409 2410 2411 2412 2413 2414 2415 2416 2418 2419 2420 2421 2422 2424 2425 2428 2431 2432 2433 2435 2436 2437 2438 2439 2440 2441 2442 2444 2445 2446 2447 2448 2449 2453 2454 2455 2457 2458 2459 2461 2462 2463 2465 2466 2467 2468 2469 2472 2473 O TRP H47 N VAL H 48 CA VAL H 48 CB VAL H 48 CG IVAL H 48 CG2 VAL H 48 C VAL H48 O VAL H48 N ALA H49 CA ALA H 49 GB ALA H 49 C ALA H49 0 ALA H49 N GLU H 50 CA GLU H 50 GB GLU H 50 CG GLU H 50 CD GLU H 50 OE1 GLU H 50 OE2 GLU H 50 C GLUHS50 O GLU H 50 N ILEH 51 CA ILE H 51 CB ILE H 51 CG2 ILE H 51 CG IILE H 51 CD ILE H 51 C ILE H51 O ILE H 51 N ARGH 52 CA ARG H 52 GB ARG H 52 CG ARG H 52 CD ARG H 52 NE ARG H 52 CZ ARG H 52 NH1 ARG H 52 NH2 ARG H 52 C ARGH 52 O ARG H 52 N LEUH 52A CA LEU H 5D~ GB LEU H 52! CG LEU H 52Y CDI LEU H 52.

CD2 LEU H 52.

C LEU H52A O LEU H52A N LYS H52B CA LYS H 52f GB LYS H 52E CG LYS H 521 CD LYS H 521 CE LYS H 52B NZ LYS H 52f C LYS H 52B O LYS H 52B N SER H 52C CA SER H 52C GB SER H 52( OG SER H 52( C SER H52C 0 SERH 52C N ASNH 53 GA ASN H 53 GB ASN H 53 CG ASN H 53 ODI ASN H 53 ND2 ASN H 53 C ASN H 53 O ASN H 53 2 ~2.989 -8.736 8.994 1.00 5.06 21.234 -9.664 8.006 1.00 6.21 21.553 -10.994 8.436 1.00 7.94 20.271 -11.532 9.165 1.00 7.86 20.199 -13.039 9.174 1.00 10.48 20.244 -10.967 10.598 1.00 4.08 22.056 11.928 7.267 1.00 8.81 23.101 -12.618 7.404 1.00 5.89 21.351-11.914 6.127 1.00 6.18 21.700 -12.813 5.035 1.00 4.66 21.208 -14.203 5.342 1.00 2.00 21.057 -12.384 3.736 1.00 5.58 20.010 -11.747 3.745 1.00 7.99 21.711 -12.787 2.620 1.00 7.04 21.177 -12.560 1.275 1.00 8.25 21.983 -11.507 0.518 1.00 9.60 23.415 -11.900 0.271 1.00 7.83 24.059 -11.043 -0.762 1.00 13.01 24.860 -11.574 -1.536 1.00 9.53 23.750 -9.830 -0.806 1.00 13.19 21.287 -13.872 0.493 1.00 6.87 22.120 -14.702 0.832 1.00 5.50 20.423 -14.049 -0.489 1.00 7.46 20.525 -15.201 -1.407 1.00 6.66 19.542 -16.318 -1.060 1.00 3.45 18.094 -15.845 -1.218 1.00 9.97 19.820 -17.559 -1.892 1.00 2.00 18.849 -18.673 -1.582 1.00 2.00 20.265 -14.716 -2.841 1.00 5.59 19.323 -13.991 -3.108 1.00 5.07 21.116 -15.123 -3.745 1.00 6.35 21.016 -14.633 -5.108 1.00 8.96 22.421 -14.501 -5.684 1.00 5.72 23.496 -14.350 -4.591 1.00 12.48 24.049 -12.963 -4.426 1.00 13.83 25.266 -12.784 -5.163 1.00 12.25 26.261 -11.942 -4.831 1.00 12.96 27.292 -11.867 -5.607 1.00 11.49 26.235 -11.166 -3.765 1.00 14.67 20.091 -15.492 -5.959 1.00 10.32 19.256 -16.204 -5.416 1.00 8.96 20.247 -15.437 -7.310 1.00 9.13 19.293 -16.088 -8.198 1.00 9.35 19.218 -15.294 -9.498 1.00 8.23 19.030 -13.759 -9.350 1.00 4.43 A 19.087 -13.099 -10.721 1.00 9.87 A 17.701 -13.450 -8.694 1.00 4.72 19.642 -17.538 -8.507 1.00 6.27 20.735 -18.003 -8.227 1.00 6.95 18.707 -18.240 -9.087 1.00 7.45 19.002 -19.570 -9.564 1.00 11.04 17.851 -20.082 -10.394 1.00 13.40 318.080 -21.505 -10.842 1.00 18.86 316.950 -22.008 -11.699 1.0021.41 17.363 -23.307 -12.408 1.00 27.85 316.327 -23.728 -13.385 1.0034.07 20.277 -19.571 -10.407 1.00 11.82 21.175 -20.365 -10.168 1.00 10.65 20.364 -18.627 -11.377 1.00 10.14 21.522 -18.520 -12.23 1 1.00 8.75 21.276 -17.513 -13.352 1.00 11.63 20.872 -16.286 -12.838 1.00 15.43 22.788 -18.173 -11.499 1.00 11.06 23.851 -18.241 -12.089 1.00 9.23 22.694 -17.799 -10.197 1.00 10.74 23.902 -17.544 -9.381 1.00 11.27 23.666 -16.359 -8.458 1.00 10.94 23.335 -15.136 -9.252 1.00 8.42 22.251 -14.580 -9.150 1.00 12.13 24.262 -14.729 -10.060 1.00 10.17 24.216 -18.790 -8.543 1.00 10.33 25.160 -18.808 -7.705 1.00 9.92 SUBSTITUTE SHEET (RULE 28) WO 99/10379 WO 9910379PCT/GB98/02542 -190-

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2474 2476 2477 2478 2479 2480 2483 2484 2485 2487 2488 2489 2490 2491 2492 2493 2494 2495 2497 2498 2499 2501 2502 2503 2504 2505 2507 2508 2509 2511 2512 2513 2514 2516 2517 2518 2519 2520 2522 2523 2525 2526 2527 2529 2530 2531 2532 2533 2534 2535 2536 2537 2539 2540 2541 2543 2544 2545 2546 2547 2549 2550 2551 2552 2553 2555 2556 2557 2559 2560 2561 2563 N ASNH 54 CA ASN H 54 GB ASN H 54 CG ASN H 54 OD I ASN H 54 ND2 ASN H 54 C ASNIH 54 O ASN H54 N TYR H 55 CA TYR H 55 GB TYR H 55 CG TYR H 55 CD I TYR H 55 GEI TYR H 55 CD2 TYR H 55 CE2 TYR H 55 CZ TYR H 55 OH TYR H 55 C TYR H 55 O TYR H 55 N ALAH 56 CA ALA H 56 GB ALA H- 56 C ALA H56 O ALAH 56 N THR H 57 CA THR H 57 GB THR H 57 OG1 THR H 57 CG2 THR H 57 C THR H 57 0 THRH 57 N HIS H58 CA HIS H 58 GB HIS H 58 CG HIS H 58 CD2 HIS H 58 NDI HISH 58 GEl HIS H 58 NE2 HIS H 58 C HIS H 58 O HISH 58 N TYR H 59 CA TYR H 59 CB TYR H 59 CG TYR H 59 CDI TYR H 59 GEl TYR H 59 CD2 TYR H 59 CE2 TYR H 59 CZ TYR H 59 OH TYR H 59 C TYR H 59 0 TYR H 59 23.439 -19.852 -8.826 1.00 10.20 23.551I -21.163 -8.120 1.00 10.20 25.011 -21.606 -7.986 1.00 6.42 25.726 -21.683 -9.341 1.00 8.73 25.244 -22.312 -10.274 1.00 8.04 26.858 -21.024 -9.453 1.00 4.73 22.950-_21.062 -6.718 1.00 11.89 23.297 -2 1.860 -5.839 1.00 12.26 22.046 -20.090 -6.524 1.00 9.38 21.484 -19.806 -5.175 1.00 8.46 20.698 -2 1.003 -4.697 1.00 2.42 19.528 -21.295 -5.577 1.00 8.11 19.5 14 -22.432 -6.404 1.00 9.49 18.407 -22.701 -7.215 1.00 12.87 18.427 -20.461 -5.589 1.00 4.03 17.335 -20.717 -6.38 1 1.00 11.68 17.325 -2 1.845 -7.207 1.00 15.91 16.234 -22.076 -8.070 1.00 20.99 22.609 -19.434 -4.168 1.00 8.90 22.572 -19.819 -2.968 1.00 12.11 23.598 -18.646 -4.647 1.00 5.77 24.707 -18.204 -3.818 1.00 7.06 25.729 -17.514 -4.713 1.00 11.84 24.215 -17.266 -2.660 1.00 7.10 23.166 -16.609 -2.757 1.00 5.63 24.970 -17.229 -1.566 1.00 7.85 24.513 -16.532 -0.373 1.00 6.03 23.978 -17.545 0.679 1.00 4.33 25.028 -18.473 1.037 1.00 3.89 22.769 -18.316 0.163 1.00 3.87 25.632 -15.8 14 0.287 1.00 4.64 26.812 -16.091 0.021 1.00 7.15 25.284 -14.850 1.141 1.00 5.83 26.293 -14.231 2.021 1.00 2.00 26.921 -12.931 1.497 1.00 4.50 27.572 -13.120 0.170 1.00 4.63 28.846 -13.287 -0.205 1.00 7.27 26.845 -13.170 -0.966 1.00 5.48 27.570 -13.365 -2.011 1.00 8.70 28.800 -13.435 -1.577 1.00 9.97 25.601 -13.989 3.345 1.00 2.00 24.381 -13.898 3.362 1.00 2.00 26.384 -13.961 4.399 1.00 3.87 25.864 -13.906 5.777 1.00 6.14 26.107 -15.252 6.467 1.00 4.65 25.271 -16.347 5.898 1.00 2.93 25.758 -17.152 4.887 1.00 7.71 24.947 -18.093 4.278 1.00 5.29 23.946 -16.515 6.295 1.00 4.20 23.149 -17.452 5.690 1.00 5.04 23.678 -18.232 4.673 1.00 5.90 22.939 -19.182 4.123 1.00 9.69 26.594 -12.892 6.574 1.00 6.82 27.761 -12.666 6.335 1.00 7.72 25.931 -12.299 7.550 1.00 8.95 26.650 -11.388 8.438 1.00 6.79 25.673 -10.579 9.283 1.00 8.53 27.503 -12.219 9.336 1.00 10.22 27.113 -13.351 9.701 1.0011.26 28.650 -11.676 9.743 1.00 13.53 29.577 -12.429 10.584 1.00 14.91 30.802 -11.573 10.930 1.00 14.40 28.908 -12.963 11.864 1.00 17.24 29.237 -14.047 12.320 1.00 21.67 ALA H 60 ALA H 60 ALA H 60 ALA H 60 ALA H 60 ALAKH 61 ALA H 61 ALA H 61 ALA H 61 ALA H 61 SER H 62 SER H 62 GB SER H 62 OG SER H 62 C SER H 62 SERKH 62 N VAL H63 CA VAL H 63 27.932 -12.239 12.405 1.00 18.88 27.306 -12.63 1 13.682 1.00 20.00 26.509 -11.457 14.200 1.00 16.39 25.622 -10.968 13.202 1.00 18.61 26.370 -13.836 13.548 1.00 21.12 25.769 -14.313 14.527 1.00 19.05 26.256 -14.333 12.352 1.00 18.08 25.250 -15.311 12.067 1.00 17.68 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -191-

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2564 2565 2566 2567 2568 2569 2571 2572 2573 2574 2575 2576 2580 2581 2582 2584 2585 2586 2587 2589 2590 2591 2592 2593 2595 2596 2599 2602 2603 2604 2606 2607 2608 2609 2610 2611 2612 2613 2614 2615 2616 2618 2619 2620 2622 2623 2624 2625 2627 2628 2629 2630 2631 2632 2633 2634 2636 2637 2638 2640 2641 2642 2644 2645 2646 2647 2648 2650 2651 2654 2657 2658 CB VAL H 63 24.137 -14.526 11.349 1.00 18.65 CG I VAL H 63 23.649 -15.184 10.084 1.00 16.99 CG2 VAL H 63 23.022 -14.241 12.351 1.00 12.88 C VAL H 63 25.837 -16.469 11.264 1.00 15.76 O VAL H 63 25.280 -17.560 11.194 1.00 14.97 N LYS H 64 27.015 -16.231 10.750 1.00 18.14 CA LYS H 64 27.685 -17.200 9.940 1.00 20.28 GB LYS H 64 29.060 -16.647 9.528 1.00 22.43 CG LYS H 64 29.192 -16.198 8.089 1.00 20.56 CD LYS H 64 30.621 -15.730 7.833 1.00 23.16 CE LYS H 64 30.812 -15.238 6.413 0.01 21.98 NZ LYS H 64 32.230 -14.876 6.134 0.01 23.60 C LYS H 64 27.845 -18.489 10.730 1.00 18.78 O LYS H 64 28.206 -18.455 11.907 1.00 20.26 N GLY H 65 27.545 -19.606 10.084 1.00 17.68 CA GLY H 65 27.676 -20.907 10.732 1.00 16.07 C GLY H 65 26.461 -21.337 11.563 1.00 14.30 0 GLY H 65 26.362 -22.497 11.930 1.00 14.97 N ARG H 66 25.536 -20.421 11.858 1.00 14.24 CA ARG H 66 24.324 -20.777 12.607 1.00 10.28 CB ARG H 66 24.245 -19.925 13.845 1.00 7.89 CG ARG-H 66 25.480 -20.0 14 14.692 1.00 7.93 CD ARG H 66 25.663 -18.698 15.446 1.00 14.73 NE ARG H 66 24.524 -18.447 16.242 1.00 17.33 CZ ARG H 66 23.908 -17.292 16.364 1.00 17.22 NHI ARG H 66 22.878 -17.269 17.125 1.00 18.44 NH-2 ARG H 66 24.306 -16.173 15.772 1.00 15.39 C ARG H 66 23.078 -20.588 11.793 1.00 9.54 O ARG H 66 22.054 -21.264 12.017 1.00 11.68 N PHE H 67 23.098 -19.625 10.874 1.00 9.08 CA PHE H 67 21.902 -19.383 10.053 1.00 8.27 GB PHE H 67 21.489 -17.883 10.070 1.00 14.66 GG PHE H 67 20.947 -17.325 11.376 1.00 11.27 CDI PHEH 67 20.920 -18.097 12.555 1.00 16. CD2 PHE H 67 20.467 -16.026 11.430 1.00 12.21 GEl PHE H 67 20.433 -17.564 13.746 1.00 15.15 CE2 PHE H 67 19.982 -15.490 12.625 1.00 16.05 CZ PHE H 67 19.968 -16.259 13.774 1.00 14.19 C PHE H 67 22.159 -19.801 8.590 1.00 8.04 O PHE H 67 23.317 -19.732 8.113 1.00 7.14 N THR H 68 21.076 -20.208 7.898 1.00 5.55 GA THR H 68 21.144 -20.637 6.500 1.00 6.31 GB THR H 68 21.151 -22.179 6.428 1.00 10.66 OGI THRH 68 22.306 -22.665 7.128 1.00 8.86 CG2 THR H 68 21.133 -22.687 4.978 1.00 10.19 C THR H 68 19.917 -20.126 5.738 1.00 6.07 O THR H 68 18.767 -20.466 6.071 1.00 9.45 N ILE H 69 20.141 -19.270 4.750 1.00 4.87 CA ILE H 69 19.049 -18.764 3.958 1.00 2.00 GB ILE H 69 19.310 -17.256 3.524 1.00 6.99 CG2 ILE H 69 20.538 -17.123 2.645 1.00 7.03 CG I ILE H 69 18.097 -16.669 2.798 1.00 2.00 CD ILE H 69 18.320 -15.236 2.400 1.00 2.00 C ILE H 69 18.897 -19.669 2.718 1.00 2.51 O ILE H 69 19.876 -20.196 2.252 1.00 2.38 N SER H 70 17.680 -19.873 2.253 1.00 2.57 CA SER H 70 17.469 -20.669 1.076 1.00 6.14 GB SER H 70 17.380 -22.175 1.448 1.00 9.52 OG SER H 70 16.268 -22.503 2.279 1.00 10.39 C SER H 70 16.207 -20.196 0.385 1.00 6.48 O SER H 70 15.460 -19.431 0.959 1.00 7.77 N ARG H 71 15.973 -20.612 -0.858 1.00 7.82 CA ARG H 71 14.761 -20.181 -1.550 1.00 8.16 GB ARG H 71 15.000 -18.914 -2.446 1.00 10.92 CG ARG H 71 15.996 -19.087 -3.614 1.00 8.76 GD ARG H 71 16.362 -17.741 -4.294 1.00 4.61 NE ARG H 71 15.191 -17.036 -4.849 1.00 7.09 CZ ARG H 71 15.228 -15.735 -5.189 1.00 7.29 NHI ARG H 71 14.156 -15.124 -5.665 1.00 8.76 NH-2 ARG H 71 16.331 -15.058 -5.011 1.00 3.13 C ARG H 71 14.174 -21.274 -2.383 1.00 9.04 0 ARG H 71 14.844 -22.180 -2.800 1 .00 11.-10 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -192-

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2659 N ASP H 72 2661 CA ASP H 72 2662 GB ASP H 72 2663 CG ASP H 72 2664 OD I ASP H 72 2665 0D2 ASP H 72 2666* C ASP H 72 2667 0 ASP H 72 2668 N ASP H 73 2670 CA ASP H 73 2671 GB ASP H 73 2672 CG ASP H 73 2673 ODI ASP H 73 2674 0D2 ASP H 73 2675 C ASP H 73 2676 -0 ASP H 73 2677 N SER H 74 2679 CA SER H 74 2680 GB SER H 74 2681 OG SER H 74 2683 C SER H 74 2684 0 SER H 74 2685 N LYS H 75 2687 CA LYS H 75 2688 GB LYS H 75 2689 CG LYS H 75 2690 CD LYS H 75 2691 CE LYS H 75 2692 NZ LYS H 75 2696 C LYS H 75 2697 0 LYS H 75 2698 N SER H 76 2700 CA SER H 76 2701 GB SER H 76 2702 OG SER H 76 2704 C SER H 76 2705 0 SER H 76 2706 N SER H 77 2708 CA SER H 77 2709 GB SER H 77 2710 OG SER H 77 2712 C SER H 77 2713 0 SER H 77 2714 N VAL H 78 2716 CA VALKH 78 2717 GB VAL H 78 2718 CG VAL H 78 2719 GG2 VAL H 78 2720 C VAL H 78 2721 0 VAL H 78 2722 N TYR H 79 2724 GA TYR H 79 2725 GB TYR H 79 2726 CG TYR H 79 2727 CDI TYR H 79 2728 GEI TYR H 79 2729 GD2 TYR H 79 2730 GE2 TYR H 79 2731 GZ TYR H 79 2732 OH TYR H 79 2734 C TYR H 79 2735 0 TYR H 79 2736 N LEU H 80 2738 CA LEU H 80 2739 GB LEU H 80 2740 CG LEU H 80 2741 CDI LEU H 80 2742 CD2 LEU H 80 2743 C LEU H 80 2744 0 LEU H 80 2745 N GLN H 81 2747 CA GLN H 81 12.918 -21.163 -2.626 1.00 8.40 12.289 -22.068 -3.482 1.00 13.86 11.481 -23.065 -2.666 1.00 18.00 10.864 -24.131 -3.538 1.00 22.29 9.974 -23.794 -4.325 1.00 18.82 11.258 -25.307 -3.419 1.00 29.08 11.420 -21.246 -4.406 1.00 12.87 10.344 -20.782 -4.047 1.00 11.56 11.919 -21.035 -5.587 1.00 14.62 11. 199 -20.236 -6.513 1.00 12.47 12.041 -19.914 -7.757 1.00 14.32 13.310 -19.140 -7.394 1.00 12.44 13.277 -18.373 -6.416 1.00 13.98 14.341 -19.3 16 -8.059 1.00 14.38 9.931 -20.899 -6.869 1.00 15.39 8.975 -20.159 -7.118 1.00 17.19 9.856 -22.293 -6.824 1.00 16.30 8.538 -22.984 -7.156 1.00 17.45 8.532 -24.599 -7.050 1.00 15.19 9.312 -25.282 -6.029 1.00 2.00 7.4 18 -22.406 -6.305 1.00 19.15 6.276 -22.222 -6.769 1.00 16.07 7.797 -22.022 -5.063 1.00 20.59 6.840 -21.532 -4.071 1.00 22.07 7.137 -22.236 -2.744 1.00 22.73 7.181 -23.747 -2.878 1.00 30.86 8.082 -24.387 -1.825 1.00 34.56 7.988 -25.896 -1.899 1.00 36.81 6.598 -26.374 -1.597 1.00 38.63 6.880 -20.022 -3.865 1.00 21.01 6.121 -19.481 -3.032 1.00 18.31 7.737 -19.329 -4.598 1.00 18.64 7.852 -17.876 -4.417 1.00 16.65 6.539 -17.182 -4.738 1.00 18.03 6.413 -16.873 -6.103 1.00 23.00 8.154 -17.593 -2.969 1.00 15.08 7.553 -16.704 -2.411 1.00 13.71 9.089 -18.353 -2.376 1.00 12.40 9.333 -18.222 -0.957 1.00 11.32 8.666 -19.385 -0.235 1.00 5.62 7.244 -19.338 -0.349 1.00 11.83 10.801 -18.209 -0.653 1.00 11.23 11.586 -18.826 -1.386 1.00 10.52 11.178 -17.438 0.380 1.00 11.36 12.557 -17.449 0.908 1.00 9.82 13.284 -16.055 0.778 1.00 2.05 12.638 -15.004 1.613 1.00 8.95 14.736 -16.175 1.126 1.00 6.47 12.439 -17.924 2.378 1.00 10.77 11.339 -17.884 2.943 1.00 10.22 13.510 -18.447 2.962 1.00 9.85 13.401 -19.059 4.298 1.0011.42 13.279 -20.578 4.167 1.00 8.95 12.223 -21.091 3.208 1.00 9.83 10.890 -21.229 3.592 1.00 13.08 9.939 -21.770 2.734 1.00 13.31 12.569 -21.502 1.923 1.00 16.54 11.640 -22.047 1.060 1.00 13.14 10.327 -22.194 1.470 1.00 15.87 9.436 -22.916 0.674 1.0021.63 14.652 -18.789 5.081 1.00 8.87 15.679 -18.519 4.485 1.00 7.96 14.561 -18.851 6.418 1.00 7.68 15.758 -18.726 7.275 1.00 6.13 15.864 -17.318 7.922 1.00 3.75 17.142 -17.034 8.797 1.00 5.89 18.360 -16.802 7.906 1.00 7.66 16.934 -15.797 9.679 1.00 7.64 15.721 -19.813 8.388 1.00 6.11 14.831 -19.837 9.212 1.00 10.81 16.662 -20.692 8.332 1.00 9.34 16.836 -21.742 9.294 1.00 7.35 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02 542 -193-

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2748 2749 2750 2751 2752 2755 2756 2757 2759 2760 2761 2762 2763 2764 2765 2766 2768 2769 2770 2771 2772 2775 2776 2777 2779 2780 2781 2782 2783 2786 2787 2788 2790 2791 2792 2793 2794 2795 2796 2797 2799 2800 2801 2802 2803 2805 2806 2809 2812 2813 2814 2816 2817 2818 2819 2820 2822 2823 2824 2825 2826 2828 2829 2830 2831 2832 2833 2834 2835 2837 2838 2839 GB GLN H 81 CG GLN H 81 CD GLN H 81 OEI GLN H 81 NE2 GLN H 81 C GLNH 81 O GLN H 81 N MET H 82 CA MET H 82 GB MET H 82 CG MET H 82 SD MET H 82 CE MET H 82 C MET H 82 O MET H 82 N ASN H 82A CA ASN H 82A GB ASN H 82A CG ASN H 82A ODI ASN H 82A ND2 ASN H 82A C ASN H 82A ASN H 82A N ASN H82B CA ASN H 82B GB ASN H 82B CG ASN H 82B ODI ASN H 82B ND2 ASN H 82B C ASN H 82B O ASN H 82B N LEU H82C CA LEU H 82C GB LEU H 82C CG LEU H 82G CDI LEU H 82C CD2 LEU H 82C C LEU H 82C 0 LEU H 82C N ARG H83 GA ARG H 83 GB ARG H 83 GG ARG H 83 CD ARG H 83 NE ARG H 83 CZ ARG H 83 NH IARG H 83 NH2 ARG H 83 C ARG H 83 0 ARG H83 N ALA H 84 CA ALA H 84 GB ALA H 84 C ALA H84 O ALA H 84 N ALA H 85 CA ALA H 85 GB ALA H 85 C ALA H 85 O ALA H 85 N ASP H 86 GA ASP H 86 GB ASP H 86 CG ASP H 86 ODI ASP H 86 0D2 ASP H 86 C ASP H86 O ASP H 86 N THR H 87 CA THR H 87 GB THR H 87 OG ITHR H 87 17.458 -22.950 8.601 1.00 10.80 17.874 -24.108 9.496 1.00 7.67 16.703 -24.581 10.254 1.00 12.30 15.676 -24.859 9.669 1.00 9.50 16.824 -24.628 11.577 1.00 14.89 17.772 -21.246 10.299 1.00 7.63 18.925 -20.973 9.982 1.00 6.37 17.327 -21.119 11.526 1.00 8.18 18.231I -20.598 12.573 1.00 8.53 17.574 -19.407 13.273 1.00 11.01 17.021 -18.404 12.305 1.00 12.29 15.941 -17.230 13.061 1.00 13.74 14.457 -18.124 12.844 1.00 14.37 18.512 -21.687 13.592 1.00 8.43 17.574 -22.300 14.079 1.00 5.71 19.784 -21.874 13.889 1.00 8.95 20.240 -22.876 14.802 1.00 11.83 21.152 -23.871 14.094 1.00 14.31 20.435 -24.642 13.030 1.00 14.14 19.202 -24.697 13.022 1.00 20.53 21.186 -25.207 12.109 1.00 19.33 21.062 -22.227 15.874 1.00 14.07 21.560 -21.114 15.685 1.00 12.90 21.232 -22.938 16.971 1.00 13.76 22.088 -22.462 18.073 1.00 17.95 23.590 -22.67 1 17.708 1.00 20.73 23.871 -24.023 16.988 1.00 29.83 23.782 -25.129 17.563 1.00 32.41 24.219 -23.953 15.704- 1.00 33. 21.759 -20.982 18.397 1.00 15.91 22.633 -20.118 18.520 1.00 12.49 20.445 -20.717 18.497 1.00 14.84 19.944 -19.382 18.758 1.00 13.25 18.409 -19.392 18.668 1.00 7.42 17.787 -19.362 17.248 1.00 7.73 16.312 -19.737 17.258 1.00 4.66 17.920 -17.971 16.669 1.00 2.94 20.473 -18.838 20.110 1.00 16.15 20.775 -19.596 21.050 1.00 17.22 20.641 -17.525 20.163 1.00 16.23 21.147 -16.838 21.318 1.00 16.47 22.474 -16.221 21.000 1.00 17.57 23.503 -17.159 20.472 1.00 23.38 24.656 -16.3 19 19.994 1.00 29.30 25.722 -17.091 19.407 1.00 30.53 26.685 -16.527 18.696 1.00 33.66 27.658 -17.280 18.201 1.00 37.56 26.680 -15.199 18.477 1.00 35.33 20.185 -15.715 21.668 1.00 17.82 19.461 -15.226 20.798 1.00 19.55 20.185 -15.255 22.900 1.00 14.91 19.254 -14.173 23.249 1.00 16.48 19.366 -13.837 24.723 1.00 15.35 19.493 -12.909 22.384 1.00 14.44 18.559 -12.129 22.125 1.00 16.17 20.748 -12.735 21.929 1.00 15.72 21.104 -11.596 21.076 1.00 15.91 22.628 -11.499 20.932 1.00 11.61 20.433 -11.691 19.678 1.00 15.42 20.438 -10.694 18.921 1.00 14.28 19.877 -12.880 19.335 1.00 12.78 19.172 -13.064 18.045 1.00 10.42 19.198 -14.509 17.571 1.00 4.96 20.590 -15.028 17.411 1.00 10.01 20.820 -16.182 17.780 1.00 12.26 21.453 -14.293 16.934 1.00 8.11 17.739 -12.640 18.142 1.00 8.78 16.999 -12.683 17.168 1.00 12.52 17.331 -12.241 19.311 1.00 8.30 15.957 -11.796 19.500 1.00 8.21 15.706 -11.463 21.037 1.00 7.33 15.888 -12.655 21.802 1.00 6.98 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -194-

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2841 CG2 THR H 87 2842 C THR H 87 2843 0 THR H 87 2844 N GLY H 88 2846 CA GLY H 88 2847 C GLY H 88 2848 0 GLY H 88 2849 N ILE H 89 2851 CA ILE H 89 2852 GB ILE H 89 2853 CG2 ILE H 89 2854 CG1I ILEKH 89 2855 CD ILE H 89 2856 C ILE H 89 2857 0 ILE H 89 2858 N TYR H 90 2860 CA TYR H 90 2861 CB TYR H 90 2862 CG TYR H 90 2863 CDI TYRH 90 2864 GEl TYR H 90 2865 CD2 TYR H 90 2866 CE2 TYR H 90 2867 CZ TYR H 90 2868 OH TYR H 90 2870 C TYR H 90 2871 0 TYR H 90 2872 N TYR H 91 2874 CA TYR H 91 2875 GB TYR H 91 2876 GG TYR H 91 2877 CDI TYRH 91 2878 GEl TYR H 91 2879 GD2 TYR H 91 2880 GE2 TYR H 91 2881 CZ TYR H 91 2882 OH TYR H 91 2884 C TYR H 91 2885 0 TYR H 91 2886 N CYS H 92 2888 CA CYS H 92 2889 GB CYS H 92 2890 SG GYS H 92 2891 C CYS H 92 2892 0 CYS H 92 2893 N THR H 93 2895 CA THR H 93 2896 CB THR H 93 2897 OG I THR H 93 2899 CG2 THR H 93 2900 C THR H 93 2901 0 THR H 93 2902 N GLY H 94 2904 CA GLY H 94 2905 C GLY H 94 2906 0 GLY H 94 2907 N VAL H 95 14.304 -10.960 21.286 1.00 5.67 15.687 -10.575 18.603 1.00 9.42 16.557 -9.719 18.446 1.00 13.23 14.533 -10.533 17.980 1.00 7.71 14.193 -9.374 17.192 1.00 9.10 13.1 13 -9.691 16.243 1.00 9.84 12.644 -10.824 16.234 1.00 7.86 12.655 -8.677 15.485 1.00 9.1 1 11.644 -8.885 14.456 1.00 10.31 10.781 -7.639 14.300 1.00 11.02 9.724 -7.873 13.233 1.00 10.51 10.139 -7.330 15.659 1.00 11.28 9.284.-6.073 15.682 1.00 17.09 12.385 -9.170 13.146 1.00 11.03 13.322 -8.442 12.807 1.00 11.03 12.039 -10.285 12.488 1.00 11.24 12.742 -10.687 13.136 -12.141 14.348 -12.417 14.286 -12.296 15.385 -12.594 15.539 -12.851 16.635 -13.147 16.544 -13.008 17.665 -13.223 11.923 -10.416 1 10.740 -10.839 12.547 -9.679 9 11.874 -9.271 11.967 -7.735 11.498 -6.910 10.185 -6.466 11.281 1.00 9.58 11.351 1.00 4.73 12.227 1.00 4.17 13.633 1.00 2.00 14.426 1.00 2.00 11.669 1.00 2.40 12.465 1.00 2.17 13.855 1.00 2.00 14.644 1.00 2.45 0.062 1.00 9.22 9.964 1.00 12.19 .131 1.00 8.92 7.878 1.00 6.94 7.705 1.00 8.51 8.859 1.00 7. 13- 8.912 1.00 6.14 9.718 -5.698 9.980 1.00 7.31 12.358 -6.571 9.896 1.00 4.90 11.889 -5.806 10.981 1.00 8.04 10.566 -5.379 11.012 1.00 5.99 10.080 -4.630 12.114 1.00 13.80 12.588 -9.873 6.643 1.00 5.68 13.811 -9.911 6.613 1.00 10.68 11.858 -10.371 5.667 1.00 5.92 12.504 -10.601 4.362 1.00 9.62 11.878 -11.758 3.625 1.00 8.20 10.133 -11.548 3.675 1.00 16.35 12.266 -9.322 3.536 1.00 7.60 11.183 -8.723 3.585 1.00 8.00 13.239 -8.913 2.792 1.00 8.87 13.129 -7.658 2.043 1.00 9.75 13.594 -6.438 2.916 1.00 7.13 13.882 -5.296 2.069 1.00 8.11 14.829 -6.781 3.713 1.00 6.38 13.999 -7.733 0.801 1.00 9.01 15.047 -8.368 0.860 1.00 8.92 13.576 -7.103 -0.311 1.00 8.19 14.410 -7.128 -1.482 1.00 9.97 13.978 -6.140 -2.538 1.00 11.34 13.075 -5.369 -2.322 1.00 8.22 14.692 -6.178 -3.672 1.00 13.48 14.458 -5.332 -4.849 1.00 10.59 13.011 -5.255 -5.260 1.00 9.92 12.943 -4.461 -6.543 1.00 12.93 12.405 -6.638 -5.477 1.00 12.57 14.999 -3.909 -4.732 1.00 12.91 14.430 -3.040 -4.058 1.00 16.60 16.114 -3.704 -5.374 1.00 14.72 16.735 -2.365 -5.516 1.00 17.50 16.907 -1.394 -4.292 1.00 15.41 16.437 -0.244 -4.355 1.00 16.20 17.5 19 -1.780 -3.174 1.00 13.46 17.941 -3.130 -2.865 1.00 13.51 19.422 -3.160 -2.463 1.00 11.95 20.404 -3.131 -3.631 1.00 15.05 20.374 -1.861 -4.476 1.00 16.43 SUBSTITTE SHEET (RULE 26) 2909 2910 2911 2912 2913 2914 2915 2917 2918 2919 2920 2922 2923 2924 2925 CA VAL H 95 GB VAL H 95 CG I VAL H 95 CG2 VAL H 95 C VAL H 95 0 VAL H 95 N GLY H96 CA GLY H 96 C GLY H96 O GLY H96 N GLN H 97 CA GLN H 97 CB GLN H 97 CG GLN H 97 CD GLN H 97 WO 99/10379 WO 9910379PCT/G B98/02 542 -195-

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2926 2927 2930 2931 2932 2934 2935 2936 2937 2938 2939 2940 2941 2942 2943 2944 2946 2947 2948 2949 2950 2952 2953 2954 2955 2956 2957 2958 2959 2960 2962 2963 2964 2966 2967 2968 2969 2970 2971 2972 2973 2975 2976 2977 2978 2979 2980 2982 2983 2984 2985 2987 2988 2989 2990 2991 2992 2995 2996 2997 2999 3000 3001 3002 3004 3005 3006 3008 3009 3010 3011 3013 OEI GLN H 97 NE2 GLN H- 97 C GLN H97 O GLN H97 N PHE H 98 CA PHE H 98 GB PHE H 98 CG PHE H 98 CD I PI-E H 98 CD2 PHE H 98 GEI PHE H 98 CE2 PHE H 98 CZ PHE H 98 C PHE H981 O PHE H98 N ALAKH 101 CA ALA H 101 GB ALA H 101 C ALA H 101 0 ALA H 101 N TYRKH 102 CA TYR H 102 GB TYR H 102 CG TYR H 102 CIDI TYR H 102 GEI TYR H 102 CD2 TYR H 102 CE2 TYR H 102 CZ TYR H 102 OH TYR H 102 C TYR H 102 O TYR H 102 N TRP H 103 CA TRP H 103 GB TRP H 103 CG TRP H 103 CD2 TRP H 103 CE2 TRP H 103 CE3 TRP H 103 CIDI TRP H 103 NEI TRP H 103 CZ2 TRP H 103 CZ3 TRP H 103 CH2 TRP H 103 C TRP H 103 O TRP H 103 N GLY H 104 CA GLY H 104 C GLYKH 104 O GLY H 104 N GLN H 105 CA GLN H 105 GB GLN H 105 CG GLN H 105 CD GLN H 105 OEI GLN H 105 NE2 GLN H 105 C GLN H 105 O GLN H 105 N GLY H 106 CA GLY H 106 C GLY H 106 O GLY H 106 N THR H 107 CA THR H 107 GB THR H 107 OG I THR H 107 CG2 THR H 107 C THR H 107 0 THR H 107 N THR H 108 CA THR H 108 20.856 -0.810 -4.064 1.00 17.08 19.826 -1.965 -5.675 1.00 18.31 17.071 -3.627 -1.687 1.00 10.81 17.133 -4.792 -1.295 1.00 8.86 16.232 -2.733 -1.171 1.00 8.60 15.370 -3.030 -0.030 1.00 8.66 16.036 -2.546 1.263 1.00 11.54 17.347 -3.195 1.612 1.00 9.16 17.375 -4.422 2.262 1.00 6.51 18.559 -2.584 1.291 1.00 9.14 18.590 -5.041 2.585 1.00 9.69 19.764 -3.190 1.617 1.00 8.35 19.785 -4.432 2.266 1.00 6.22 [4.061 -2.278 -0.191 1.00 10.16 13.591 -1.636 0.736 1.00 11.80 13.475 -2.339 -1.365 1.00 9.29 12.250 -1.634 -1.622 1.00 8.04 11.991 -1.549 -3.111 1.00 6.69 11.074 -2.298 -0.962 1.00 11.49 10.142 -1.595 -0.529 1.00 11.63 11.101 -3.645 -0.923 1.00 8.89 9.998 -4.417 -0.365 1.00 13.48 9.566 -5.515 -1.327 1.00 17.64 9.270 -5.035 -2.711 1.00 19.49 8.742 -3.765 -2.921 1.00 19.65 8.440 -3.311 -4.190 1.00 19.68 9.498 -5.856 -3.816 1.0021.83 9.193 -5.399 -5.093 1.00 24.66 8.658 -4.126 -5.266 1.0021.57 8.255 -3.706 -6.526 1.00 29.25 10.410 -5.062 0.923 1.00 10.63 11.507 -5.608 1.019 1.00 10.52 9.522 -4.971 1.884 1.00 12.90 9.734 -5.491 3.246 1.00 12.06 9.979 -4.325 4.256 1.00 10.97 11.293 -3.613 4.125 1.00 7.64 12.445 -3.715 5.028 1.00 7.34 13.461 -2.945 4.476 1.00 2.00 12.692 -4.388 6.241 1.00 2.00 11.676 -2.790 3.109 1.00 2.00 12.957 -2.399 3.334 1.00 5.49 14.718 -2.824 5.073 1.00 6.14 13.922 -4.274 6.837 1.00 4.72 14.930 -3.503 6.264 1.00 4.93 8.450 -6.196 3.663 1.00 10.58 7.349 -5.699 3.367 1.00 12.28 8.555 -7.366 4.288 1.00 9.92 7.338 -7.982 4.799 1.00 8.86 6.892 -7.280 6.088 1.00 11.03 7.500 -6.276 6.495 1.00 7.62 5.872 -7.822 6.744 1.00 14.11 5.368 -7.248 7.997 1.00 13.52 3.900 -7.701 8.254 1.00 16.08 3.725 -9.073 8.885 1.00 16.34 4.174 -10.239 8.022 1.00 17.73 4.238 -10.158 6.808 1.00 21.14 4.489 -11.338 8.655 1.00 22.59 6.271 -7.593 9.179 1.00 13.99 6.235 -6.907 10.203 1.00 12.82 7.108 -8.638 9.007 1.00 13.67 8.032 -9.058 10.049 1.00 11.11 7.440 -10.150 10.927 1.00 12.32 6.213 -10.266 11.071 1.0011.02 8.303 -10.969 11.489 1.00 14.65 7.861 -12.050 12.387 1.00 12.73 7.916 -13.415 11.638 1.00 10.15 7.388 -14.451 12.478 1.00 15.55 9.320 -13.770 11.204 1.00 4.69 8.746 -12.030 13.619 1.00 10.17 9.951 -11.941 13.485 1.00 10.87 8.174 -12.063 14.843 1.00 12.24 9.036 -11.947 16.022 1.00 10.94 SUBSTITUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -196-

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3014 3015 3017 3018 3019 3020 3022 3023 3024 3025 3026 3027 3028 3030 3031 3032 3034 3035 3036 3037 3039 3040 3041 3042 3043 3044 3045 3047 3048 3049 3051 3052 3053 3055 3056 3057 3059 3060 3061 3063 3064 3065 3066 3067 3069 3070 3071 3072 3073 3074 3078 3079 3080 3082 3083 3084 3086 3087 3088 3089 3091 3092 3093 3095 3096 3097 3098 3099 3100 3101 3102 3103 CB THR H 108 OG I THR H 108 CG2 THR H 108 C THR H 108 0 THR H 108 N VAL H 109 CA VAL H 109 GB VAL H 109 GI VAL H 109 GG2 VAL H 109 C VAL H 109 O VAL H 109 N THRH 110 GA THR H 110 GB THR H 110 OGI THR H 110 GG2 THR H 110 C THRH 110 O THRH 110 N VALH 111 CA VAL H I111 GB VAL H I111 CGI VAL H I111 GG2 VAL H 111 C VALH 111 O VALH 111 N SERH 112 CA SERH 112 GB SER H 112 OG SER H 112 C SERH 112 O. SER H 112 N SERH 113 GA SER H 113 GB SER H 113 OG SER H 113 C SER H 113 O SERH 113 N ALA H 114 GA ALA H 114 GB ALA H 114 C ALA H 114 O ALA H 114 N LYSH 115 GA LYS H 115 GB LYS H 115 GG LYS H 115 GD LYS H 115 GE LYS H 115 NZ LYS H 115 C LYS H115 0 LYS H115 N THR H 116 GA THRH 116 GB THRH 116 OGI THRH 116 CG2 THR H 116 C THRH 116 0 THRH 116 N THRH 117 GA THRH 117 GB THRH 117 OGI THR H 117 CG2 THR H 117 C THRH 117 THRH 117 N PRO H 118 CD PRO H 118 GA PRO H 118 GB PRO H 118 C G PRO H 118 C PROHII8 8.392-11.090 17.206 1.00 12.32 9.309-10.902 18.318 1.00 13.78 7.162-11.704 17.736 1.00 15.73 9.597-13.283 16.497 1.00 9.14 8.928-14.325 16.556 1.00 6.78 10.857 -13.228 16.755 1.00 8.85 11.603 -14.334 17.259 1.00 9.39 12.782-14.660 16.313 1.00 11.58 13.746 -15.632 16.965 1.00 5.51 12.254-15.239 14.982 1.00 10.69 12.175-13.884 18.594 1.0012.15 12.918-12.923 18.638 1.00 12.01 11.785-_14.562 19.680 1.0011.46 12.309 -14.249 21.010 1.00 11.24 11. 175 -14.060 22.037 LOO0 9.63 10.208 -13.127 21.544 1.00 10.83 11.740 -13.573 23.346 1.00 8.99 13.144 -15.405 21.498 1.00 7.60 12.661-16.519 21.509 1.00 12.38 14.372-15.151 21.857 1.00 9.00 15.227 -16.192 22.420 1.00 12.99 16.640 -16.282 21.736 1.00 10.01 17.398 -17.484 22.286 1.00 8.99 16.505 -16.383 20.206 1.00 14.22 15.458 -15.895 23.918 1.00 13.42 16.267-15.051 24.277 1.00 14.03 14.806 -16.618 24.779 1.00 15.10 14.993 -16.380 26.185 1.00 17.45 13.871 -15.496 26.699 1.00 17.57 14.114 -15.136 28.034 1.00 18.71 14.966-17.667 26.953 1.00 18.74 14.136 -18.525 26.687 1.0021.32 15.847 -17.795 27.926 1.00 22.03 15.794 -18.957 28.828 1.00 26.34 17.205 -19.273 29.321 1.00 28.00 17.811 -18.109 29.887 1.00 35.95 14.818-18.759 30.049 1.0026.98 14.673 -19.666 30.891 1.0026.75 14.144 -17.583 30.119 1.0025.34 13.242-17.263 31.218 1.00 23.14 12.860-15.786 31.184 1.00 22.38 11.977 -18.113 31.210 1.0024.60 11.415 -18.438 30.137 1.0024.23 11.514 -18.449 32.436 1.0023.35 10.315 -19.244 32.615 1.0023.70 10.461 -20.136 33.834 1.00 24.56 11.658 -21.039 33.758 1.00 31.61 11.624 -22.085 34.863 1.00 37.03 12.721 -23.133 34.688 1.00 36.28 12.668 -24.162 35.769 1.00 37.66 9.095 -18.361 32.786 1.00 21.83 9.202 -17.207 33.182 1.00 19.35 7.929-18.915 32.513 1.0022.54 6.719-18.145 32.646 1.0025.02 5.481 -18.992 32.343 1.00 28.05 5.582 -19.477 30.988 1.00 31.99 4.195 -18.183 32.500 1.00 25.98 6.667 -17.602 34.036 1.00 23.95 7.072 -18.274 34.977 1.00 23.92 6.225 -16.385 34.168 1.00 24.46 6.255 -15.706 35.461 1.00 22.17 7.605 -15.005 35.649 1.00 22.94 8.671 -15.961 35.443 1.00 19.91 7.730 -14.4 14 37.043 1.00 25.03 5.135-14.686 35.504 1.0022.41 5.031 -13.806 34.631 1.0022.33 4.236 -14.811 36.481 1.0021.47 4.285 -15.779 37.622 1.00 24.37 3.128-13.886 36.620 1.00 19.44 2.249 -14.585 37.664 1.00 21.47 3.274 -15.198 38.569 1.00 23.59 3.744 -12.593 37.114 1.00 16.22 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -197-

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3 104 3 105 3106 3107 3108 3 109 3110 3111 3112 3114 3115 3116 3118 3119 3120 3121 3123 3124 3125 3126 3127 3128 3129 3131 3132 3133 3134 3135 3136 3137 3138 3139 3141 3142 3143 3144 3145 3146 3147 3148 3149 3150 3152 3153 3154 3155 3156 3157 3158 3159 3161 3162 3163 3164 3165 3166 3167 3168 3169 3170 3171 3172 3174 3175 3176 3177 3178 3179 3180 3183 3185 3186 O PRO H 118 N PRO H 119 CD PRO H 119 CA PRO H 119 GB PRO H1119 CG PRO H 119 C PRO H 119 O PRO H 119 N THR H 120 CA THR H 120 GB THR H 120 OG I THR H 120 CG2 THR H 120 C THR H 120 0 THR H 120 N VAL H 121 CA VAL H 121 GB VAL H 121 CG I VAL H 121 CG2 VAL H 121 C VAL H 121 O VAL H 121 N TYR H 122 CA TYR H 122 GB TYR H 122 CG TYR H 122 CD I TYR H 122 GElI TYR H 122 CD2 TYR H 122 CE2 TYR H 122 CZ TYR H 122 OH TYR H 122 C TYR H 122 0 TYR H 122 N PRO H 123 CD PRO H 123 CA PRO H 123 GB PRO H 123 CG PRO H 123 C PRO H 123 O PROHI123 N LEU H 124 CA LEU H 124 GB LEU H 124 CG LEU H 124 CD I LEU H 124 CD2 LEU H 124 C LEU H 124 0 LEU H 124 N ALA H 125 CA ALA H 125 GB ALA H 125 C ALA H 125 O ALA H 125 N PRO H 126 CD PRO H 126 CA PRO H 126 GB PRO H 126 CG PRO H 126 C PRO H 126 0 PRO H 126 N GLY H 127 GA GLYKH 127 C GLY H 127 OTI GLY H 127 On2 GLY H 127 GB ALA H 134 C ALA H 134 O ALA H 134 N ALA H 134 CA ALA H 134 N MET H 135 4.804 -12.624 37.750 1.00 13.84 3.181 -11.442 36.814 1.00 14.35 1.959 -11.207 36.027 1.00 14.96 3.775 -10.192 37.278 1.00 14.79 3.119 -9.167 36.378 1.00 13.18 1.742 -9.716 36.246 1.00 13.05 3.420 -9.954 38.716 1.00 13.65 2.351 -10.392 39.166 1.00 14.64 4.281 -9.290 39.445 1.00 13.96 3.852 -8.825 40.759 1.00 12.82 4.974 -8.766 41.783 1.00 5.50 5.854 -7.766 4 1.423 1.00 20.74 5.743 -10.044 41.845 1.00 8.80 3.343 -7.454 40.486 1.00 8.85 4.065 -6.662 39.870 1.00 10.44 2.070 -7.208 40.783 1.00 11.59 1.455 -5.896 40.488 1.00 8.52 0.011 -6.064 40.025 1.00 6.26 -0.610 -4.713 39.693 1.00 3.84 -0.004 -6.987 38.822 1.00 9.50 1.522 -4.968 41.701 1.00 12.01 1.283 -5.388 42.839 1.00 10.41 1.871 -3.715 4.1.459. 1.00 11.35 2.094 -2.768-42.551 1.00 11.02 3.597 -2.475 42.697 1.00 7.81 4.422 -3.681 43.099 1.00 15.44 4.080 -4.436 44.244 1.00 16.70 4.846 -5.523 44.662 1.00 12.55 5.553 -4.057 42.382 1.00 7.91 6.328 -5.128 42.784 1.00 8.28 5.977 -5.861 43.932 1.00 11.52 6.815 -6.850 44.397 1.00 11.02 1.359 -1.504 42.255 1.00 12.61 1.438 -0.973 41.184 1.00 11.44 0.606 -1.001 43.195 1.00 18.80 0.485 -1.489 44.591 1.00 19.13 -0.164 0.223 43.008 1.00 18.57 -1.109 0.182 44.199 1.00 15.86 -0.191 -0.319 45.247 1.00 19.34 0.769 1.403 43.074 1.00 18.37 1.773 1.373 43.802 1.00 24.31 0.477 2.416 42.305 1.00 17.89 1.270 3.628 42.346 1.00 18.57 1.954 3.898 41.015 1.00 17.71 2.962 2.838 40.535 1.0020.67 3.662 3.341 39.297 1.00 18.20 3.950 2.459 41.651 1.00 18.24 0.396 4.805 42.758 1.00 18.06 -0.483 5.272 41.994 1.00 14.26 0.589 5.2 14 44.013 1.00 18.65 -0.168 6.314 44.583 1.00 16.82 -0.580 6.007 46.029 1.00 13.74 0.682 7.548 44.523 1.00 15.68 1.896 7.462 44.551 1.00 16.41 0.059 8.704 44.406 1.00 16.40 -1.415 8.893 44.331 1.00 13.85 0.771 9.978 44.333 1.00 16.02 -0.372 11.000 44.314 1.00 15.53 -1.481 10.224 43.672 1.00 14.07 1.740 10.188 45.498 1.00 18.31 1.461 9.848 46.671 1.00 16.34 2.878 10.736 45.166 1.00 22.48 3.860 11.012 46.166 1.00 30.63 3.583 12.326 46.845 1.00 33.75 4.359 13.283 46.589 1.00 39.27 2.581 12.409 47.625 1.00 35.28 -7.921 19.962 39.302 1.00 21.74 -8.377 17.5 10 39.469 1.00 25.40 -9.457 16.953 39.269 1.00 26.02 -7.261 18.732 41.332 1.00 24.67 -8.291 18.835 40.244 1.00 23.36 -7.229 17.059 38.997 1.00 24.22 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -198- ATOM3

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1188 1189 1190 1191 1192 3193 3194 1195 3197 3198 3199 3200 3201 3202 3203 3205 3206 3207 3209 3210 3211 3212 3214 3215 3216 3217 3218 3219 3220 3221 3223 3224 3225 3226 3228 3229 3230 3231 3232 3233 3235 3236 3237 3238 3239 3240 3241 3242 3244 3245 3246 3247 3248 3249 3250 3252 3253 3254 3255 3256 3257 3261 326' 3263 326~ 326 326' 326 327( 327 327: 327: CA MET H 135 GB MET H 135 CG MET!-H 135 SD MET H 135 CE MET H 135 C MET H 135 0 MET H 135 N VAL H 136 CA VAL H 136 CB VAL H 136 CG I VAL H 136 CG2 VAL H 136 C VAL H 136 O VAL H 136 N T1-RH- 137 CA THR H 137 GB THR H 137 OG I THR H 137 CG2 THR H 137 C THR H 137 O THR H 137 N LEU H 138 CA LEU H 138 GB LEU H 138 CG LEU H 138 CDI LEU H 138 CD2 LEU H 138 C LEU H 138 O LEU H 138 N GLY H 139 CA GLY H 139 C GLY H 139 0 GLY H 139 N CYS H 140 CA CYS H 140 GB CYS H 140 SG CYS H 140 C CYS H 140 O CYS H 140 N LEU H 141 CA LEU H 141 GB LEU H 141 CG LEU H 141 CDI LEU H 141 CD2 LEU H 141 C LEU H 141 O LEU H 141 N VAL H 142 CA VAL H 142 GB VAL H 142 CG1I VAL H 142 CG2 VAL H 142 C VALHI142 0 VALHI142 N LYSHI143 CA LYS H 143 GB LYS H 143 CG LYS H 143 CD LYS H 143 CE LYS H 143 NZ LYS H 143 IC LYS H 143 0O LYSHI143 IN GLYHI144 5 CA GLY H 144 S C GLYHl144 7 0 GLYHI144 8 N TYRHI145 0 CA TYRKH 145 1 GB TYR H 145 2 CG TYR H 145 3 CD I TYR H 145 -7.095 15.775 38.333 1.00 26.09 -6.684 15.971 36.852 1.00 30.45 -7.835 16.193 35.855 1.00 34.99 -8.958 14.753 35.759 1.00 46.83 -8.784 14.2 16 34.059 1.00 42.78 -5.978 15.070 39.074 1.00 25.74 -5.028 15.734 39.523 1.00 25.90 -6.074 13.773 39.258 1.00 22.09 -5.001 13.072 39.935 1.00 18.97 -5.429 12.618 41.367 1.00 16.24 -6.694 11.797 41.355 1.00 15.37 -4.297 11.870 42.020 1.00 16.51 -4.555 11.889 39.100 1.00 17.30 -5.397 11.220 38.485 1.00 17.97 -3.245 11.643 39.035 1.00 17.82 -2.783 10.483 38.276 1.00 18.38 -1.73 1 10.855 37.238 1.00 15.72 -2.3 13 11.857 36.384 1.00 16.58 -1.374 9.644 36.382 1.00 13.21 -2.287 9.336 39.164 1.00 16.41 -1.405 9.514 40.023 1.00 14.38 -2.924 8.182 38.940 1.00 13.46 -2.617 6.950 39.647 1.00 11.93 -3.897 6.401 40.222 1.00 9.54 -4.690 7.402 41.030 1.00 9.64 -5.943 6.750 41.531 1.00 11.85 -3.839 7.920 42.174 1.00 6.56 -2.046 5.964 38.649 1.00 12.78 -2.281 6.106 37.457 1.00 10.57 -1.316 4.988 39.106 1.00 11.80 -0.770 4.041 38.174 1.00 11.77 -0.578 2.682 38.763 1.00 14.58 -0.863 2.452 39.936 1.00 14.52 -0.090 1.781 37.952 1.00 13.05 0.182 0.447 38.375 1.00 12.15 -0.942 -0.487 37.970 1.00 15.82 -1.991 -0.935 39.377 1.00 30.05 1.438 -0.028 37.762 1.00 9.66 1.589 0.121 36.548 1.00 8.35 2.337 -0.555 38.594 1.00 6.85 3.554 -1.210 38.112 1.00 10.45 4.728 -1.024 39.075 1.00 3.00 6.061 -1.672 38.701 1.00 7.34 6.581 -1.153 37.363 1.00 7.63 7.091 -1.374 39.751 1.00 2.28 3.299 -2.708 37.948 1.00 9.22 2.819 -3.363 38.869 1.00 8.85 3.550 -3.220 36.751 1.00 10.01 3.449 -4.641 36.484 1.00 7.47 2.629 -4.891 35.208 1.00 10.12 2.421 -6.409 34.967 1.00 8.96 1.282 -4.167 35.330 1.00 6.58 4.880 ;.5.167 36.351 1.00 11.16 5.513 -5.101 35.263 1.00 6.29 5.393 -5.690 37.460 1.00 9.75 6.804 -6.016 37.537 1.00 12.16 7.348 -5.453 38.844 1.00 9.61 8.868 -5.354 38.937 1.00 9.64 9.275 -4.918 40.340 1.00 11.17 10.793 -4.938 40.495 1.00 15.36 11.200 -5.003 41.925 1.00 13.08 7.158 -7.514 37.403 1.00 14.70 6.437 -8.400 37.861 1.00 17.80 8.250 -7.745 36.687 1.00 16.56 8.881 -9.067 36.594 1.00 18.62 8.089 -10.220 36.006 1.00 16.58 8.190 -11.328 36.517 1.0020.26 7.362 -10.004 34.922 1.00 15.03 6.614 -11.103 34.286 1.00 12.99 5.208 -10.660 33.827 1.00 10.99 5.135 -9.584 32.771 1.00 13.14 5.416 -8.267 33.096 1.00 15.73 SUBSTITIUTI SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -199-

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3274 3275 3276 3277 3278 3280 3281 3282 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 3295 3296 3297 3298 3299 3300 3301 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3314 3315 3316 3317 3318 3320 3321 3322 3323 3324 3325 3326 3328 3329 3330 3332 3333 3334 3335 3337 3338 3339 3340 3341 3342 3343 3345 3346 3347 3349 3350 3351 3352 3354 3355 CEI TYR H 145 CD2 TYR H 145 CE2 TYR H 145 CZ TYR H 145 OH TYR H 145 C TYR H 145 O TYR H 145 N PHE H 146 CA PHE H 146 CB PHE H 146 CG PHE H 146 CD I PHE H 146 CD2 PHE H 146 CElI PHE H 146 CE2 PHE H 146 CZ PHE H 146 C PHE H 146 0 PHE H 146 N PRO H 147 CD PRO H 147 CA PRO H 147 CB PRO H 147 CG PRO H 147 C PRO H 147 PRO H 147 N GLU H 148 CA GLU H 148 CB GLU H 148 CG GLU H 148 CD GLU H 148 OEI GLU H 148 0E2 GLU H 148 C GLU H 148 0 GLU H 148- N PRO H 149 CD PRO H 149 CA PRO H 149 CB PRO H 149 CG PRO H 149 C PRO H 149 O PRO H 149 N VAL H 150 CA VAL H 150 CB VAL H 150 CG I VAL H 150 CG2 VAL H 150 C VAL H 150 0 VAL H 150 N THR H 151 CA THR H 151 CB THR H 151 OG I THR H 151 CG2 THR H 151 C THR H 151 O THR H 151 N VAL H 152 CA VAL H 152 CB VAL H 152 CG I VAL H 152 CG2 VAL H 152 C VAL H 152 0 VAL H 152 N THR H 153 CA THR H 153 CB THR H 153 OG I THR H 153 CG2 THR H 153 C THR H 153 O THR H 153 N TRP H 154 CA TRP H 154 CB TRP H 154 5.282 -7.258 32.165 1.00 12.07 4.716 -9.850 3 1.460 1.00 15.71 4.582 -8.826 30.509 1.00 9.54 4.873 -7.534 30.876 1.00 10.77 4.831 -6.497 29.946 1.00 9.76 7.377 -11.654 33.088 1.00 13.49 8.359 -11.074 32.659 1.00 12.72 6.944 -12.803 32.602 1.00 16.82 7.473 -13.382 3 1.370 1.00 18.55 8.904 -13.878 31.511 1.00 18.86 9.4 12 -14.458 30.205 1.00 23.23 10.213 -13.700 29.365 1.00 25.00 8.973 -15.715 29.749 1.00 24.90 10.555 -14.162 28.084 1.00 26.32 9.304 -16.185 28.488 1.00 26.32 10.092 -15.407 27.646 1.0025.16 6.649 -14.556 3 1.022 1.00 19.54 6.362 -15.325 31.931 1.00 18. 6.212 -14.746 29.719 1.0021.47 4.947 -15.427 29.403 1.00 21.60 6.425 -13.870 28.551 1.0021.86 6.189 -14.884 27.403 1.0021.39 5.240 -15.912 28.012 1.00 19.80 5.429 -12.695 28.485 1.00 18.87 4.635 -12.5 17 29.377 1.00 15.77 5.418 -11.983 27.333 1.00 19.05 4.398 -10.982 27.056 1.00 19.21 4.970 -9.897 26.157 1.00 17.80 6.120 -9.149 26.752 1.00 15.35 6.491 -7.960 25.920 1.00 19.90 7.608 -7.957 25.354 1.00 23.72 5.670 -7.015 25.826 1.00 17.13 3.287 -11.666 26.280 1.00 19.80 3.495 -12.766 25.824 1.00 21.47 2.074 -11.085 26.123 1.00 19.34 0.842 -11.841 25.966 1.00 15.47 1.637 -9.812 26.659 1.00 18.47 0.524 -9.460 25.678 1.00 18.21 0.018-10.824 25.214 1,0017.1.6 1.103 -9.887 28.117 1.00 18.85 1.155 -10.899 28.823 1.00 16.35 0.418 -8.814 28.427 1.00 19.66 -0.234 -8.572 29.679 1.00 16.78 0.816 -7.977 30.670 1.00 16.55 0.488 -6.566 31.077 1.00 17.59 0.998 -8.878 3 1.854 1.00 13.17 -1.324 -7.580 29.302 1.00 16.49 -1.165 -6.832 28.343 1.00 18.33 -2.459 -7.653 29.919 1.00 14.32 -3.527 -6.716 29.637 1.00 14.69 -4.778 -7.448 29.097 1.00 17.81 -5.351 -8.263 30.141 1.00 22.14 -4.396 -8.364 27.922 1.00 20.30 -3.899 -5.978 30.920 1.00 13.72 -4.195 -6.613 31.921 1.00 13.94 -3.912 -4.657 30.864 1.00 12.98 -4.175 -3.843 32.041 1.00 12.73 -2.967 -2.947 32.373 1.00 11.49 -3.279 -2.108 33.610 1.00 11.37 -1.719 -3.792 32.608 1.00 9.03 -5.401 -2.965 31.864 1.00 15.95 -5.481 -2.170 30.914 1.00 19.74 -6.370 -3.124 32.770 1.00 19.44 -7.587 -2.324 32.746 1.00 19.80 -8.820 -3.223 32.528 1.00 21.72 -8.652 -4.4 12 33.286 1.00 26.52 -8.974 -3.597 31.063 1.00 21.56 -7.761 -1.521 34.064 1.00 17.98 -7.047 -1.744 35.043 1.00 17.86 -8.681 -0.562 34.054 1.00 18.02 -8.954 0.231 35.232 1.00 16.37 -8.438 1.620 35.052 1.00 15.29 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -200-

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3356 3357 3358 3359 3360 3361 3363 3364 3365 3366 3367 3368 3370 3371 3372 3373 3374 3377 3378 3379 3381 3382 3383 3385 3386 3387 3389 3390 3391 3392 3394 3395 3396 3398 3399 3400 3402 3403 3404 3405 3406 3407 3408 3409 3411 3412 3413 3414 3415 3417 3418 3419 3421 3422 3423 3425 3426 3427 3428 3430 3431 3432 3433 3434 3435 3436 3438 3439 3440 3441 3442 3444 CG TRP H 154 CD2 TRP H 154 CE2 TRP H 154 CE3 TRP H 154 CDI TRP H 154 NEI TRP H 154 CZ2 TRP H 154 CD3 TRP H 154 CH2 TRP H 154 C TRP H 154 0 TRP H 154 N ASN H 155 CA ASN H 155 GB ASN H 155 CG ASN H 155 OD I ASN H 155 ND2 ASN H 155 C ASN H 155 O ASN H 155 N SER H 156 CA SER H 156 CB SER H 156 OG SER H 156 C SER H 156 0 SER H 156 N GLY H 157 CA GLY H 157 C GLY H 157 0 GLY H 157 N SERH 158 CA SER H 158 C1B SER H 158 OG SER H 158 C SERH 158 0 SER H 158 N LEU H 159 CA LEU H 159 C1B LEU H 159 CG LEU H 159 CD1 LEU H 159 CD2 LEU H 159 C LEU H 159 LEU H 159 N ALA H 160 CA ALA H 160 GB3 ALA H 160 C ALA H 160 O ALA H 160 N SER H 161 CA SER H 161 GB SER H 161 OG SER H 161 C SER H 161 O SER H 161 N GLY H 162 CA GLY H 162 C GLY H 162 0 GLY H 162 N VAL H 163 CA VAL H 163 GB VAL H 163 CG I VAL H 163 CG2 VAL H 163 C VAL H 163 O VAL H 163 N HIS H 164 CA HIS H 164 C1B HIS H 164 CG HIS H 164 CD2 HIS H 164 NDI HIS H 164 GEl HIS H 164 -6.960 -6.070 -4.766 -6.261 -6.189 -4.881 -3.652 -5.153 -3.865 -10.423 -11.208 -10.781 1.649 34.987 1.827 36.097 1.906 35.577 1.950 37.493 1.608 33.866 1.763 34.225 2.112 36.377 2.164 38.288 2.247 37.720 0.226 35.482 0.444 34.565 -0.062 36.722 1.00 14.01 1.00 14.22 1.00 12.55 1.00 13.71 1.00 13.72 1.00 14.65 1.00 11.60 1.00 13.74 1.00 15.50 1.00 16.57 1.00 19.07 1.00 18.63 -12.177 -0.278 37.117 1.00 19.34 -12.895 1.047 37.330 1.00 19.07 -12.499 1.668 38.658 1.00 19.37 -11.818 1.048 39.479 1.00 17.72 -12.904 2.898 38.869 1.00 21.85 -12.902 -1.167 36.114 1.00 20.59 -13.989 -0.851 35.645 1.00 19.83 -12.232 -2.290 35.767 1.00 22.94 -12.740 -3.255 34.801 1.00 23.80 -14.028 -3.890 35.333 1.00 24.08 -13.778 -4.574 36.550 1.00 23.19 -12.968 -2.650 33.393 1.00 26.88 -13.730 -3.185 32.575 1.0029.20 -12.293 -1.561 33.090 1.0026.24 -12.488 -0.966 31.798 1.00 28.52 -13.553 0.129 31.789 1.00 28.13 -13.793 0.740 30.74 1 1.00 28.70 -14.194 0.371 32.945 1.00 27.82 -15.164 1.445 33.049 1.0027.17 -16.045 1.301 34.334 1.00 28.51 -15.342 1.560 35.537 1.00 25.88 -14.420 2.768 33.007 1.00 27.55 -14.947 3.772 32.555 1.00 28.23 -13.177 2.753 33.491 1.00 29.42 -12.295 3.898 33.352 1.00 30.68 -11.288 3.966 34.495 1.00 31.18 -11.756 4.650 35.788 1.0029.87 -10.635 4.657 36.8 19 1.00 34.45 -12.186 6.067 35.491 1.00 29.03 -11.571 3.717 32.042 1.00 31.97 -10.554 3.036 31.980 1.0031.21 -12.168 4.261 30.990 1.00 34.61 -11.634 4.120 29.629 1.00 35.80 -12.804 3.926 28.668 1.00 34.51 -10.776 5.337 29.226 1.00 35.27 -9.611 5.209 28.796 1.00 34.38 -11.347 6.517 29.381 1.00 33.77 -10.624 7.747 29.083 1.00 33.98 -11.613 8.911 29.028 1.0033.96 -12.943 8.420 28.847 1.00 38.30 -9.560 8.020 30.155 1.00 30.88 -9.693 7.603 31.314 1.00 32.73 -8.502 8.702 29.765 1.00 28.58 -7.480 9.082 30.742 1.00 23.36 -6.467 8.005 3 1.081 1.00 19.44 -5.669 8.193 32.016 1.00 17.19 -6.462 6.913 30.296 1.00 16.90 -5.546 5.808 30.529 1.00 14.28 -6.243 4.469 30.285 1.00 11.19 -5.256 3.321 30.477 1.00 9.55 -7.402 4.343 31.259 1.00 8.14 -4.318 5.896 29.644 1.00 16.70 -4.409 6.341 28.504 1.00 20.46 -3.190 5.493 30.176 1.00 12.44 -1.964 5.449 29.434 1.00 12.24 -1.048 6.574 29.835 1.00 12.04 -1.363 7.839 29.187 1.00 17.45 -1.795 9.016 29.683 1.00 16.45 1. 111 8.058 27.848 1.00 19.78 -1.345 9.283 27.520 1.00 18.88 SUBSTITUTE SHEET (RULE 2B) WO 99/10379 WO 9910379PCT/GB98/02542 1-

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3445 3447 3448 3449 3451 3452 3453 3455 3456 3457 3458 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 3470 3471 3472 3473 3474 3475 3476 3477 3479 3480 3481 3482 3483 3485 3486 3487 3488 3489 3490 3491 3493 3494 3495 3496 3497 3498 3499 3500 3502 3503 3504 3505 3506 3507 3510 3511 3512 3514 3515 3516 3517 3518 3520 3521 3522 3523 3524 3 526 3527 3 528 3 529 NE2 HIS H 164 C HIS H 164 0 HIS H 164 N THR H 165 CA THR H 165 GB THR H 165 OG I THR H 165 CG2 THR H 165 C THR H 165 O THR H 165 N PHE H 166 CA PHE H 166 GB3 PHE H 166 CG PHE H 166 CDI PHE H 166 CD2 PHE H 166 GElI PHE H 166 GE2 PHE H 166 CZ PHE H 166 C PHE H 166 O PHE H 166 N PRO H 167 CD PRO H 167 CA PRO H 167 GB PRO H 167 CG PRO H 167 C PRO H 167 0 PRO H 167 N ALA H 168 CA ALA H 168 GB ALA H 168 C ALA H 168 0 ALA H 168 N VAL H 169 CA VAL H 169 GB3 VAL H 169 CG I VAL H 169 CG2 VAL H W6 C VAL H 169 O VAL H 169 N LEU H 170 CA LEU H 170 GB3 LEU H 170 CG LEU H 170 CD1 LEU H 170 CD2 LEU H 170 C LEU H 170 O LEU H 170 N GLN H 171 CA GLN H 171 GB GLN H 171 CG GLN H 171 CD GLN H 171 OE1 GLN H 17 NE2 GLN H 17 C GLN H 171 O GLN H 171 N ALA H 172 CA ALA H172 GB ALA H172 C ALA H 172 O ALA H 172 N ALA H 173 CA ALA H 17 GB ALA HI17 C ALA H 173 0 ALA H 173 N LEUHI174 GA LEU H 17' GB3 LEU H 174 CG LEU H 17~ ICDI LEU H 17 -1.749 9.883 28.620 1.00 19.92 -1.249 4.202 29.775 1.00 12.66 -0.920 4.010 30.928 1.00 12.50 -1.023 3.327 28.830 1.00 12.38 -0.198 2.176 29.140 1.00 10.10 -0.932 0.859 28.952 1.00 9.55 -2.129 0.919 29.729 1.00 11.21 -0.086 -0.307 29.427 1.00 8.04 1.047 2.227 28.3 13 1.00 11.67 0.973 2.441 27.118 1.00 10.32 2.188 2.057 28.992 1.00 11.57 3.508 2.196 28.398 1.00 12.01 4.399 2.957 29.415 1.00 9.65 3.773 4.286 29.831 1.00 8.07 2.850 4.349 30.874 1.00 4.17 4.009 5.459 29.082 1.00 10.68 2.156 5.542 31.164 1.00 8.24 3.318 6.659 29.363 1.00 11.02 2.385 6.699 30.401 1.00 5.44 4.110 0.820 28.001 1.00 15.40 3.559 -0.237 -28.381 1.00 16.48 5.212 0.823 27.173 1.00 14.51 5.834 2.019 26.553 1.00 14.57 5.902 -0.394 26.687 1.00 13.56 6.851 0.140 25.578 1.00 15.95 6.300 1.475 25.231 1.00 15.19 6.713 -1.111 27.754 1.00 13.70 7.304 -0.467 28.629 1.00 8.91 6.768 -2.446 27.620 1.00 14.48 7.525 -3.290 28.526 1.00 13.11 7.259 -4.768 28.238 1.00 12.04 8.998 -3.015 28.403 1.00 15.12 9.5 10 -2.693 27.324 1.00 14.20 9.674 -3.048 29.527 1.00 14.23 11.092 -2.935 29.530 1.00 11.53 11.646 -1.809 30.491 1.00 10.77 11.409 -0.432 29.901 1.00 5.38 10.977 -1.881 31.846 1.00 8.65 11.580 -4.290 29.967 1.00 14.43 10.866 -4.984 30.681 1.00 13.16 12.733 -4.698 29.458 1.00 16.49 13.360 -5.934 29.890 1.00 20.55 13.982 -6.690,28.693 1.00 17.41 14.389 -8.169 28.93 1 1.00 16.89 13.177 -8.978 29.315 1.00 11.20 15.030 -8.777 27.68 1 1.00 13.43 14.432 -5.611 30.913 1.0021.20 15.435 -4.967 30.608 1.00 23.98 14.191 -6.002 32.149 1.00 25.48 15.171 -5.804 33.183 1.00 27.97 14.922 -4.486 33.992 1.00 33.14 13.467 -4.032 34.231 1.00 35.78 13.348 -2.498 34.464 1.00 41.72 1 14.208 -1.718 34.023 1.0043.19 1 12.286 -2.049 35.139 1.00 39.50 15.236 -7.032 34.075 1.00 30.85 14.308 -7.309 34.845 1.00 30.30 16.311 -7.811 33.886 1.0030.98 16.565 -9.035 34.683 1.00 32.89 16.048 -8.870 36.135 1.00 34.56 15.964 -10.296 34.037 1.00 32.42 15.562 -11.243 34.745 1.0033.51 15.975 -10.316 32.681 1.0028.84 3 15.362-11.388 31.898 1.0024.12 15.866-12.773 32.316 1.0024.73 13.846 -11.340 31.998 1.0022.90 13.168 -12.169 31.422 1.00 24.63 13.301 -10.353 32.701 1.00 19.03 11.859 -10.286 32.881 1.00 16.09 11.495 -10.523 34.374 1.00 13.53 t 11.811 -11.911 35.012 1.00 13.70 4 11.331 -11.910 36.473 1.00 13.19 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -202-

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3530 3531 3532 3533 3535 3536 3537 3538 3539 3540 3541 3542 3543 3545 3546 3547 3549 3550 3551 3553 3554 3555 3556 3558 3559 3560 3561 3562 3563 3564 3565 3567 3568 3569 3571 3572 3573 3575 3576 3577 3579 3580 3581 3583 3584 3585 3587 3588 3589 3591 3592 3593 3594 3595 3596 3597 3599 3600 3601 3603 3604 3605 3606 3608 3609 3610C 3611 361 3613 361 361 361 CD2 LEU H 174 C LEU H 174 0 LEU H 174 N TYR H 175 CA TYR H 175 CB TYR H 175 CG TYR H 175 CD I TYR H 175 GEI TYR H 175 CD2 TYR H 175 CE2 TYR H 175 CZ TYR H 175 OH TYR H 175 C TYR H 175 O TYR H 175 N THR H 176 CA THR H 176 GB THR H 176 OG I THR H 176 CG2 THR H 176 C THR H 176 O THR H 176 N LEU H 177 CA LEU H 177 GB LEU H 177 CG LEU H 177 CD I LEU H 177 CD2 LEU H 177 C LEU H 177 0 LEU H 177 N SER H 178 CA SER H 178 GB SER H 178 OG SER H 178 C SER H 178 0 SER H 178 N SERMH 179 CA SER H 179 GB SER H 179 OG SER H 179 C SERHI179 O SER H 179 N SER H 180 CA SER H 180 CB SER H 180 OG SER H 180 C SER H 180 O SER H 180 N VAL H 181 CA VAL H 181 GB VAL H 181 CG 1 VAL H 181 CG2 VAL H 181 C VAL H 181 O VAL H 181 N THR H 182 CA THR H 182 GB THR H 182 OG I THR H 182 CG2 THR H 182 C THRHI182 0 THRHI182 iN VALHI183 1 CA VAL H 183 GB VAL H 183 CG1IVAL H 183 CG2 VAL H 183 C VALHI183 50 VAL H 183 IN PRO H184 5CD PRO H 184 5 CA PROMH 184 11.119-13.044 34.233 1.00 7.07 11.362 -8.938 32.423 1.00 11.64 12.101 -7.992 32.465 1.00 13.03 10.141 -8.885 31.993 1.00 11.45 9.528 -7.647 3 1.500 1.00 13.69 8.486 _7.939 30.415 1.00 13.82 9.037 -8.570 29.180 1.00 14.75 9.958 -7.891 28.408 1.00 17.41 10.501 -8.438 27.254 1.00 18.34 8.648 -9.834 28.779 1.00 18.01 9.177-_10.401 27.619 1.0020.37 10.111 -9.689 26.860 1.00 19.65 10.636-10.221 25.713 1.0021.14 8.792 -6.860 32.607 1.00 16.88 8.132 -7.440 33.503 1.00 15.69 8.837 -5.537 32.473 1.00 14.27 8.140 -4.643 33.386 1.00 13.28 9.132 -3.928 34.356 1.00 11.07 9.739 -4.862 35.272 1.00 9.99 8.402 -2.859 35.144 1.00 7.94 7.416 -3.575 32.590 1.00 11.40 8.006 -2.982 31.696 1.00 10.96 6.149 -3.354 32.842 1.00 9.44 5.521 -2.199 32.219 1.00 11.96 4.761 -2.522 30.908 1.00 12.44 3.533 -3.426 30.906 1.00 13.51 2.348 -2.763 31.614 1.00 16.92 3.147 -3.709 29.455 1.00 19.97 4.690 -1.441 33.227 1.00 11.72 4.676 1.805 34.410 1.00 12.02 4.086 -0.366 32.806 1.00 9.83 3.269 0.430 33.698 1.00 12.66 4.026 1.657 34.240 1.00 16.23 5.018 1.303 35.164 1.0021.15 2.070 0.944 32.978 1.00 11.78 2.032 0.978 3 1.750 1.00 12.05 1.112 1.350 33.755 1.00 10.09 -0.072 1.975 33.256 1.00 9.78 -1.203 0.965 33.162 1.00 7.12 -2.348 1.479 32.502 1.00 13.99 -0.424 3.060 34.240 1.00 11.73 0.023 3.028 35.402 1.00 10.99 -1.190 4.008 33.791 1.00 12.62 -1.623 5.095 34.634 1.00 11.78 -0.620 6.257 34.502 1.00 15.26 -0.740 6.935 33.258 1.00 15.98 -3.036 5.542 34.226 1.00 11.26 -3.404 5.337 33.078 1.00 12.64 -3.845 6.053 35.189 1.00 12.70 -5.145 6.681 34.903 1.00 12.65 -6.398 6.141 35.610 1.00 14.52 -7.464 5.805 34.614 1.00 8.51 -6.095 5.069 36.613 1.00 15.67 -5.132 8.053 35.502 1.00 13.40 -4.566 8.240 36.557 1.00 10.66 -5.823 8.979 34.847 1.00 15.42 -6.030 10.289 35.405 1.00 12.05 -5.479 11.385 34.498 1.00 12.00 -4.067 11.178 34.367 1.00 12.34 -5.725 12.775 35.097 1.00 10.88 -7.500 10.451 35.616 1.00 15.30 -8.3 17 10.224 34.692 1.00 15.69 -7.839 10.749 36.868 1.00 15.89 -9.228 10.916 37.295 1.00 15.70 -9.692 9.764 38.256 1.00 13.11 -9.836 8.464 37.491 1.00 16.73 -8.703 9.586 39.372 1.00 7.49 -9.376 12.225 38.045 1.00 14.30 -8.403 12.765 38.527 1.00 15.26 -10.595 12.766 38.162 1.00 15.74 -11.858 12.234 37.661 1.00 15.39 -10.802 14.004 38.892 1.00 16.30 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -203-

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3617 3618 3619 3620 3621 3623 3624 3625 3627 3628 3629 3631 3632 3633 3635 3636 3637 3639 3640 3641 3643 3644 3645 3646 3648 3649 3650 3651 3652 3653 3654 3655 3657 3658 3659 3660 3661 3662 3663 3664 3665 3666 3667 3668 3669 3671 3672 3673 3675 3676 3677 3679 3680 3681 3682 3683 3684 3685 3686 3687 3689 3690 3691 3693 3694 3695 369( 3691 369' 370( 370 370: CB PRO H 184 CG PRO H 184 C PRO H 184 0 PRO H 184 N SER H 185 GA SER H 185 CB SER H 185 OG SER H 185 C SER H 185 0 SER H 185 N SER H 186 CA SER H 186 GB SER H 186 OG SER H 186 C SER H 186 O SER H 186 N THR H 187 GA THR H 187 GB THR H 187 OG I THR H 187 CG2 THR H 187 C THR H 187 O THR H 187 N TRP H 188 CA TRP H 188 GB TRP H 188 GG TRP H 188 GD2 TRP H 188 GE2 TRP H 188 GE3 TRP H 188 CD1 TRP H 188 NEI TRP H 188 GZ2 TRP H 188 CD3TRP H 188 CH2 TRP H 188 C TRP H 188 0 TRP H 188 N PRO H 189 GD PRO H 189 CA PRO H 189 GB PRO H 189 CG PRO H 189 C PRO H 189 O PRO H 189 N SER H 190 GA SER H 190 GB SER H 190 OG SER H 190 G SER H 190 O SER H 190 N GLU H 191 GA GLU H 191 GB GLU H 191 GG GLU H 191 CD GLU H 191 OEI GLU H 19' 0E2 GLU H 19 C GLU H191 0 GLU H191 N THRHI192 C A THR H 192 GB THR H 192 OGI THR H 19 ICG2 THR H19 IC THRHI192 0O THR H192 )N VALHI193 G A VAL H 193 GB VAL H 193 CGI VAL H 19 1 GG2 VAL H19 2 C VALHI193 -12.304 14.274 38.739 1.00 15.06 -12.679 13.484 37.534 1.00 15.56 -10.444 13.704 40.330 1.00 15.62 -10.863 12.702 40.860 1.00 17.90 -9.670 14.539 40.949 1.0021.17 -9.293 14.319 42.331 1.0023.69 -8.349 15.428 42.797 1.00 26.61 -8.816 16.703 42.357 1.00 31.23 -10.519 14.255 43.250 1.00 26.32 -10.428 13.761 44.375 1.00 29.50 -11.680 14.744 42.806 1.00 25.25 -12.862 14.639 43.647 1.00 25.46 -14.002 15.509 43.091 1.00 26.27 -14.525 15.018 41.851 1.00 29.82 -13.341 13.173 43.770 1.00 24.07 -14.195 12.888 44.575 1.0024.17 -12.784 12.249 42.971 1.00 21.70 -13.287 10.862 42.968 1.00 21.99 -13.730 10.442 41.555 1.00 20.90 -12.589 10.451 40.677 1.00 18.99 -14.774 11.407 41.023 1.00 18.74 -12.261 9.848 43.494 1.00 23.01 -12.477 8.628 43.470 1.00 23.61 -11.140 10.363 43.936 1.00 20.48 -10.135 9.556 44.546 1.00 21.24 -9.142 8.943 43.524 1.00 15.29 -8.158 7.982 44.185 1.00 11.67 -6.862 8.304 44.783 1.00 8.04 -6.334 7.115 45.311 1.00 8.99 -6.107 9.487 44.935 1.00 8.90 -8.345 6.630 44.385 1.00 13.61 -7.250 6.131 45.054 1.00 14.95 -5.089 7.066 45.964 1.00 12.53 -4.885 9.441 45.589 1.00 10.52 -4.381 8.232 46.093 1.00 12.29 -9.392 10.449 45.511 1.00 20.69 -8.948 11.534 45.134 1.0020.70 -9.142 9.960 46.713 1.00 20.09 -8.34 1 10.639 47.755 1.00 22.74 -9.520 8.612 47.148 1.00 20.72 -8.458 8.316 48.180 1.0022.60 -8.350 9.627 48.879 1.00 20.47 -10.913 8.372 47.708 1.00 21.08 -11.095 7.388 48.390 1.00 22.85 -11.898 9.205 47.432 1.0023.42 -13.249 8.934 47.944 1.00 21.96 -14.176 10.098 47.640 1.00 23.31 -14.449 10.189 46.244 1.00 23.23 -13.824 7.671 47.323 1.00 24.54 -14.591 6.939 47.994 1.00 25.15 -13.505 7.444 46.003 1.00 25.58 -13.961 6.235 45.287 1.00 23.69 -14.754 6.554 43.999 1.00 25.22 -15.884 7.588 44.164 1.00 28.53 -16.949 7.225 45.207 1.00 28.30 1-16.826 6.164 45.856 1.00 31.06 1-17.917 8.006 45.375 1.00 26.40 -12.796 5.366 44.937 1.00 23.74 -11.652 5.824 44.872 1.00 21.49 -13.097 4.115 44.698 1.00 20.79 *-12.071 3.133 44.454 1.00 21.97 -12.594 1.711 44.731 1.0023.80 2 -13.011 1.628 46.109 1.00 29.80 2 -11.496 0.677 44.486 1.00 27.22 -11.549 3.169 43.053 1.00 18.87 -12.317 3.268 42.099 1.00 15.94 -10.239 3.094 42.950 1.00 16.81 -9.591 2.917 41.671 1.00 16.97 -8.778 4.194 41.194 1.00 16.54 3 -7.944 3.904 39.924 1.00 11.61 3 -9.780 5.326 40.894 1.00 14.87 -8.725 1.643 41.776 1.00 16.78 SUBSTITUTE- SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02 542 -204-

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3703 3704 3706 3707 3708 3710 3711 3712 3713 3715 3716 3717 3718 3719 3720 3722 3723 3724 3725 3726 3729 3730 3731 3733 3734 3735 3736 3737 3738 3739 3741 3742 3743 3744 3745 3747 3748 3749 3750 3751 3753 3754 3756 3757 3758 3759 3760 3761 3762 3763 3764 3765 3767 3768 3769 3770 3771 3773 3774 3775 3777 3778 3779 3781 3782 3783 3784 3785 3787 3788 3789 3791 O VAL H 193 N THR H 194 CA THR H 194 CB THR H 194 OG I THR H 194 CG2 THR H 194 C THRI-H 194 O THR H 194 N CYS H 195 GA CYS H 195 GB CYS H 195 SG CYS H 195 C CYS H 195 O CYS H 195 N ASN H 196 CA ASN H 196 GB ASN H 196 CG ASN H 196 ODI ASN H 196 ND2 ASN H 196 C ASN H 196 O ASN H 196 N VAL H 197 CA VAL H 197 C1B VALKH 197 CG I VAL H 197 GG2 VAL H 197 C VAL H 197 O VALIH 197 N ALA H 198 GA ALA H 198 GB3 ALA H 198 C, ALA H 198 0 ALA H 198 N HIS H 199 GA HIS H 199 GB HIS H 199 CG HIS H 199 CD2 HIS H 199 ND1 HIS H 199 GEl HIS H 199 NE2 HIS H 199 C HIS H 199 O HIS H 199 N PRO H200 GD PRO H200 GA PRO H200 GB3 PRO H 200 CG PRO H 200 C PRO H200 O PRO H200 N ALAH 201 CA ALA H 201 GB ALA H 201 C ALA H 201 O ALA H 201 N SER H202 GA SER H 202 GB SER H 202 OG SER H 202 G SERH 202 O SERH 202 N ALAH 203 GA ALA H 203 GB ALAH 203 G ALA H203 O ALAH 203 N THRH 204 GA THR H204 GB3 THR H 204 OG ITHRH 204 GG2 THR H 204 -7.889 1.501 42.643 1.00 14.37 -9.032 0.687 40.931 1.00 18.51 -8.347 -0.574 40.934 1.00 19.26 -9.341 -1.665 41.316 1.00 19.05 10.064 -1.248 42.490 1.00 22. -8.644 -2.983 41.590 1.00 17.95 -7.867 -0.855 39.526 1.00 20.35 -8.574 -0.556 38.558 1.00 18.99 -6.671 -1.388 39.397 1.0022.03 -6.231 -1.850 38.101 1.00 21.55 -4.827 -1.383 37.796 1.00 22.21 -3.5 18 -2.342 38.560 1.00 26.24 -6.308 -3.366 38.063 1.00 20.83 -6.010 -4.064 39.046 1.00 21.96 -6.718 -3.855 36.927 1.00 19.29 -6.918 -5.285 36.687 1.00 16.40 -8.285 -5.444 36.035 1.00 16.17 -9.245 -4.402 36.544 1.00 13.27 -9.644 -3.478 35.833 1.00 20.19 -9.601 -4.529 37.793 1.00 11.17 -5.865 -5.762 35.703 1.00 16.19 -5.877 -5.335 34.560 1.00 13.42 -4.938 -6.594 36.149 1.00 15.57 -3.888 -7.065 35.275 1.00 14.42 -2.508 -6.855 35.888 1.00 9.60 -1.452 -7.394 34.943 1.00 7.11 -2.269 -5.382 36.162 1.00 12.01 -4.036 -8.543 34.954 1.00 16.35 -4.130 -9.370 35.872 1.00 14.56 -4.039 -8.871 33.646 1.00 17.13 -4.125 -10.267 33.222 1.00 16.34 -5.306 -10.470 32.3 19 1.00 17.48 -2.866 -10.680 32.506 1.00 18.98 -2.326 -9.928 31.688 1.00 18.73 -2.355 -11.850 32.864 1.00 18.76 -1.185 -12.410 32.209 1.00 17.07 -0.031 -12.507 33.168 1.00 8.69 1.221 -12.958 32.491 1.00 13.16 1.798 -12.594 31.293 1.00 11.24 2.094 -13.865 33.052 1.00 12.67 3.159 -14.054 32.275 1.00 15.05 2.979 -13.293 31.211 1.00 9.04 1.561 -13.804 31.708 1.00 20.77 -1.319-14.821 32.406 1.0022.61 -2.194-13.865 30.504 1.0023.38 -2.490 -12.708 29.606 1.00 23.82 -2.642-15.118 29.886 1.0022.74 -2.776 -14.742 28.420 1.00 23.09 -3.296 -13.344 28.504 1.0023.84 -1.680-16.267 30.112 1.0022.03 -2.105 -17.306 30.542 1.00 25.71 -0.392 -16.059 29.881 1.00 21.74 0.595 -17.135 30.006 1.00 22.02 1.975 -16.601 29.722 1.00 21.34 0.587 -17.840 31.379 1.0025.49 0.600 -19.086 3 1.456 1.00 27.00 0.590 -17.056 32.458 1.00 23.97 0.551 -17.620 33.806 1.00 23.02 1.084 -16.580 34.768 1.00 20.89 0.362-15.375 34.574 1.0022.36 -0.886 -17.950 34.191 1.0022.44 -1.162 -18.406 35.288 1.0024.26 -1.795 -17.698 33.281 1.0023.52 -3.21 1-17.834 33.554 1.00 24.82 -3.592-19.312 33.629 1.0025.98 -3.609 -17.062 34.843 1.00 28.71 -4.389 -17.541 35.682 1.0033.42 -3.105 -15.844 35.003 1.0027.17 -3.456-15.069 36.191 1.0027.24 -2.236 -14.718 36.997 1.00 26.73 *-1.363-13.914 36.205 1.0029.32 -1.511-15.983 37.415 1.0030.85 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -205-

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3792 3793 3794 3796 3797 3798 3799 3800 3801 3805 3806 3807 3809 3810 3811 3812 3813 3814 3815 3817 3818 3819 3820 3821 3822 3823 3824 3826 3827 3828 3829 3830 3832 3833 3834 3835 3836 3837 3841 3842 3843 3845 3846 3847 3848 3849 3850 3851 3852 3854 3855 3856 3857 3858 3859 3860 3861 3862 3863 3864 3865 3866 3867 3869 3870 3871 3872 3873 3875 3876 3879 3882 C THRH 204 0 THR H204 N LYS H205 GA LYS H 205 GB LYSH 205 GG LYS H 205 CD LYS H 205 CE LYS H 205 NZ LYS H 205 C LYSH 205 O LYS H205 N VAL H206 GA VAL H206 GB VALH 206 CG I VAL H206 CG2 VAL H 206 C VALH 206 O VALH 206 N ASPH 207 CA ASP H 207 GB ASP H 207 GG ASP H 207 OD I ASP H 207 0D2 ASP H 207 C ASPH 207 O ASP H207 N ALA H208 CA ALA H 208 GB ALA H 208 C ALAH 208 O ALAH 208 N LYSH 209 CA LYS H 209 GB LYS H 209 GG LYS H209 GD LYS H 209 GE LYSH 209 NZ LYS H 209 C LYS H209 0 LYSH 209 N ILE H210 GA ILE H210 GB ILE H210 GG2 ILE H210 G ILE H 210 GD ILE H210 G ILEH210 0 ILEH210 N VAL H211 GA VAL H211 GB VAL H211 GI VAL H211 GG2 VAL H 211 G VALH 211 0 VAL H211 N PRO H212 GD PRO H 212 GA PRO H 212 GB PRO H 212 GG PRO H 212 G PRO H212 O PRO H212 N ARG H213 GA ARGH 213 GB ARG H213 GG ARG H213 GD ARG H213 NE ARG H213 CZ ARG H213 NHI ARG H 21~ NH-2 ARG H 21 C ARG H213 -4.184 -13.774 35.844 1.00 28.10 -4.013 -13.205 34.749 1.00 27.08 -4.988 -13.325 36.796 1.00 29.70 -5.789 -12.107 36.657 1.00 29.70 -7.157 -12.465 36.050 1.00 26.59 -8.091 -11.304 35.756 1.00 30.12 -7.386 -10.115 35.126 1.0032.29 -8.357 -9.001 34.726 1.00 28.46 -9.140 -9.329 33.482 1.00 32.30 -5.905 -11.468 38.047 1.00 29.50 -6.666 -11.937 38.903 1.00 29.82 -5.086 -10.427 38.273 1.00 27.91 -5.028 -9.777 39.556 1.00 27.55 -3.558 -9.752 40.106 1.00 27.51 -2.894 -11.102 39.902 1.00 29.90 -2.746 -8.647 39.462 1.00 25.31 -5.608 -8.349 39.561 1.00 26.86 -5.512 -7.615 38.590 1.00 25.39 -6.237 -7.996 40.683 1.00 27.63 -6.74 1 -6.650 40.923 1.00 25.50 -8.170 -6.687 41.430 1.00 28.55 -9.155 -6.937 40.330 1.00 29.54 -8.722 -7.007 39.163 1.00 36.07 -10.359 -7.064 40.621 1.00 32.67 -5.917 -6.004 41.988 1.00 24.44 -5.558 -6.682 42.958 1.00 23.66 -5.604 -4.711 41.808 1.00 21.43 -4.900 -3.949 42.830 1.00 17.91 -3.418 -3.791 42.505 1.00 20.11 -5.549 -2.577 43.033 1.00 16.62 -5.643 -1.754 42.093 1.00 10.62 -6.048 -2.360 44.266 1.00 16.90 -6.670 -1.077 44.630 1.00 15.48 -7.658 -1.223 45.807 1.00 10.13 -8.246 0.110 46.195 0.50 10.96 -9.147 -0.015 47.400 0.50 14.26 -9.549 1.352 47.908 0.50 12.83 -10.556 1.242 48.990 0.50 14.36 -5.614 -0.010 44.948 1.00 12.92 -4.631 -0.266 45.641 1.00 10.83 -5.785 1.178 44.388 1.00 12.54 -4.840 2.249 4.672 1.00 14.57 -4.665 3.261 43.478 1.00 10.03 -3.416 4.066 43.683 1.00 9.58 -4.626 2.544 42.096 1.00 11.38 -3.475 1.591 41.874 1.00 9.16 -5.370 2.972 45.914 1.00 16.98 -6.520 3.462 45.931 1.00 18.38 -4.544 2.945 46.936 1.00 19.13 -4.827 3.524 48.248 1.00 20.34 -4.668 2.412 49.313 1.00 21.28 -4.884 2.972 50.722 1.00 25.89 -5.624 1.268 49.025 1.00 18.88 -3.794 4.628 48.528 1.00 19.87 -2.612 4.467 48.205 1.00 20.58 -4.185 5.764 49.138 1.00 21.21 -5.552 6.108 49.602 1.00 18.81 -3.239 6.879 49.416 1.00 20.72 -4.124 7.924 50.083 1.00 18.51 -5.473 7.608 49.550 1.00 18.18 -2.105 6.454 50.335 1.00 23.63 -2.305 5.569 51.173 1.00 27.07 -0.907 7.050 50.156 1.00 24.57 0.202 6.768 5 1.064 1.00 26.72 1.594 6.820 50.368 1.00 27.15 1.881 7.964 49.394 1.00 33.85 3.294 7.833 48.788 1.00 33.12 3.507 6.488 48.238 1.00 40.88 4.598 5.7 13 48.492 1.00 40.65 3 4.653 4,479 47.981 1.00 39.58 3 5.635 6.171 49.213 1.00 37.54 0. 157 7.700 52.274 1.00 27.92 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -206-

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3883 OTI ARG H 213 0.571 7.257 53.377 1.00 31.74 3884 0T2 ARG H 213 -0.333 8.846 52.120 1.00 29.09 3885 CB ALA P 2 31.230 -8.005 -6.156 1.00 23.82 3886 C ALA P 2 29.841 -5.882 -6.164 1.00 18.78 3887 0 ALA P 2 29.790 -5.466 -5.0 14 1.00 18.94 3890 N ALA P 2 32.320 -5.788 -6.175 1.00 24.56 3892 CA ALA P 2 31.130 -6.567 -6.663 1.00 20.94 3893 N ALA P 3 28.823 -5.793 -7.033 1.00 15.73 3895 CA ALA P 3 27.589 -5.071 -6.738 1.00 14,42 3896 CB ALA P 3 27.052 -4.456 -8.026 1.00 13.90 3897 C ALA P 3 26.482 -5.937 -6.142 1.00 14.34 3898 0 ALA P 3 26.488 -7.186 -6.247 1.00 12.83 3899 N PRO P 4 25.526 -5.262 -5.467 1.00 12.41 3900 CD PRO P 4 25.574 -3.831 -5.096 1.00 10.70 3901 CA PROP 4 24.357 -5.901 -4.882 1.00 9.09 3902 CB PRO P 4 23.878 -4.858 -3.887 1.00 10.23 3903 CG PRO P 4 24.156 -3.611 -4.622 1.00 10.28 3904 C PRO P 4 23.348 -6.156 -6.006 1.00 8.50 3905 0 PRO P 4 23.721 -6.099 -7.155 1.00 12.29 3906 N ASP P 5 22.112 -6.430 -5.714 1.00 3.44 3908 CA ASP P 5 21.183 -6.689 -6.752 1.00 6.24 3909 CB ASP P 5 19.985 -7.497 -6.235 1.00 4.87 3910 CG ASP P 5 18.944 -7.827 -7.325 1.00 8.73 3911 ODI ASP P 5 19.267 -7.802 -8.566 1.00 5.17 3912 OD2 ASP P 5 17.791 -8.100 -6.961 1.00 6.00 3913 C ASP P 5 20.723 -5.380 -7.397 1.00 11.49 3914 0 ASP P 5 19.844 -4.711 -6.901 1.00 13.66 3915 N TI-R P 6 21.312 -5.037 -8.536 1.00 13.74 3917 CA THR P 6 20.982 -3.798 -9.202 1.00 13.90 3918 CB THR P 6 22.265 -3.139 -9.756 1.00 13.32 3919 OGI THRP 6 22.906 -3.998 -10.711 1.00 19.82 3921 CG2 THR P 6 23.249 -2.904 -8.6 18 1.00 17.80 3922 C THRP 6 19.950 -3.963 -10.307 1.00 13.91 3923 0 T1IR P 6 19.797 -3.065 -11.140 1.00 16.59 3924 N ARG P 7 19.218 -5.085 -10.346 1.00 12.22 3926 CA ARG P 7 18.215 -5.219 -11.389 1.00 12.33 3927 CB ARG P 7 17.668 -6.648 -11.528 1.00 11.79 3928 CG ARG P 7 16.434 -6.709 -12.418 1.00 14.75 3929 CD ARG P 7 15.734 -8.048 -12.427 1.00 18.52 3930 NE ARG P 7 16.524 -9.011 -13.140 1.00 27.19 3932 CZ ARG P 7 16.088 -9.705 -14.179 1.0026.31 3933 NHI ARG P 7 16.917 -10.544 -14.764 1.00 31.37 3936 NH2 ARG P 7 14.850 -9.578 -14.628 1.00 25.93 3939 C ARG P 7 17.075 -4.264 -11.100 1.00 15.83 3940 0 ARG P 7 16.766 -4.007 -9.92 1 1.00 15.84 3941 N PRO P 8 16.456 -3.660 -12.161 1.00 15.86 3942 CD PROP 8 16.842 -3.743 -13.611 1.00 15.67 3943 CA PRO P 8 15.351 -2.743 -11.991 1.00 11.60 3944 CB PRO P 8 15.111 -2.160 -13.407 1.00 16.26 3945 CG PRO P 8 16.425 -2.376 -14.102 1.00 12.50 3946 C PRO P 8 14.108 -3.457 -11.438 1.00 15.08 3947 0 PROP 8 13.722 -4.583 -11.855 1.00 7.39 3948 N ALA P 9 13.531 -2.772 -10.458 1.00 14.65 3950 CA ALA P 9 12.334 -3.19 1 -9.773 1.00 16.28 3951 CB ALA P 9 12.055 -2.157 -8.654 1.00 13.79 3952 C ALA P 9 11.159 -3.193 -10.733 1.00 17.17 3953 0 ALA P 9 11.212 -2.524 -11.754 1.00 19.75 3954 N PRO P 10 10.139 -4.010 -10.493 1.00 17.47 3955 CD PRO P 10 10.126 -5.169 -9.587 1.00 17.04 3956 CA PRO P 10 8.958 -3.975 -11.315 1.0020.33 3957 CB PRO P 10 8.080 -5.081 -10.728 1.00 14.66 3958 CG PRO P 10 8.673 -5.374 -9.408 1.00 18.16 3959 C PRO P 10 8.307 -2.555 -11.248 1.0023.98 3960 OTI PROP 10 8.684 -1.768 -10.339 1.00 29.12 3961 OT2 PRO P 10 7.456 -2.226 -12.120 1.00 32.81 3962 0H2 WAT W 1 6.426 14.867 -4.480 1.00 14.28 3965 OH2 WAT W 2 17.532 -23.833 -4.169 1.00 21.81 3968 OH2 WAT W 3 18.622 4.070 58.161 1.00 6.32 3971 OH2 WAT W 4 25.532 3.202 -6.059 1.00 13.58 3974 0H2 WAT W 5 16.979 -5.181 -7.499 1.00 13.00 3977 OH2 WAT W 6 24.971 -23.001 6.210 1.00 30.37 3980 OH2 WAT W 7 21.577 -21.666 -1.335 1.00 3.40 SUBSTITUTE SHEET (RULE 2B) WO 99/10379 PCT/GB98/02542 -207-

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3983 3986 3989 3992 3995 3998 4001 4004 4007 4010 4013 4016 4019 4022 4025 4028 4031 4034 4037 4040 4043 4046 4049 4052 4055 4058 4061 4064 4067 4070 4073 4076 4079 4082 4085 4088 4091 4094 4097 4100 4103 4106 4109 4112 4115 4118 4121 4124 4127 4130 4133 4136 4139 4142 4145 4148 4151 4154 4157 4160 4163 4166 4169 4172 4175 4178 4181 4184 4187 4190 4193 4196 OH2WATW 8 OH2WATW 9 OH2WATW 10 OH2WATW I I OH2WATW 12 OH2WATW 13 OH2WATW 14 OH2WATW 15 OH2WATW 16 OH2WATW 17 OH2WATW 18 OH2WATW 19 OH2 WAT W 20 OH2WATW 21 OH2 WAT W 22 OH2 WAT W 23 OH2 WAT W 24 OH2 WAT W 25 OH2 WAT W 26 OH2 WAT W 27 OH2 WAT W 28 OH2 WAT W 29 OH2 WAT W 30 OH2WATW 31 OH2 WAT W 32 OH2 WAT W 33 OH2 WAT W 34 OH2 WAT W 35 OH2 WAT W 36 OH2 WAT W 37 OH2 WAT W 38 OH2 WAT W 39 OH2 WAT W 40 OH2WATW 41 OH2 WAT W 42 OH2 WAT W 43 OH2 WAT W 44 OH2 WAT W 45 OH2 WAT W 46 OH2 WAT W 47 OH2 WAT W 48 OH2 WAT W 49 OH2 WAT W 50 OH2WATW 51I OH2 WAT W 52 OH2 WAT W 53 OH2 WAT W 54 OH2 WAT W 55 OH2 WAT W 56 OH2 WAT W 57 OH2 WAT W 58 OH2 WAT W 59 OH2 WAT W 60 OH2WATW 61 OH2 WAT W 62 OH2 WAT W 63 OH2 WAT W 64 OH2 WAT W 65 OH2 WAT W 66 OH2 WAT W 67 OH2 WAT W 68 OH2 WAT W 69 OH2 WAT W 70 OH2WATW 71 OH2 WAT W 72 OH2 WAT W 73 OH2 WAT W 74 OH2 WAT W 75 OH2 WAT W 76 OH2 WAT W 77 OH2 WAT W 78 OH2 WAT W 79 -3.006 -3.287 28.222 1.00 30.92 28.986-11.555 3.882 1.00 9.44 -1.960 11.311 49.070 1.0032.00 8.423 -21.487 8.622 1.00 13.78 13.684 27.060 30.432 1.00 39.32 3.579 4.654 44.811 1.00 13.19 1.208 15.938 14.282 1.0022.53 12.850-17.174 34.625 1.00 19.15 10.906 -8.230 -12.637 1.0021.26 8.121-14.509 21.168 1.0037.92 21.322 7.473 14.563 1.00 18.86 -1.612 1.908 47.043 1.00 15.06 16.800 9.409 27.271 1.00 14.21 20.637 12.454 -7.154 1.00 16.36 7.902-12.529 25.324 1.00 10.64 -3.580 16.239 24.865 1.0033.41 33.184 3.198 45.354 1.00 8.24 -12.001 -7.854 37.177 1.0026.57 25.811 12.550 -5.985 1.0021.74 -2.669 4.036 26.084 1.00 17.07 7.584 17.991 41.795 1.0022.01 23.880-14.784 24.981 1.00 8.54 31.343 -2.339 -1.788 1.00 19.31 17.604 7.877 16.208 1.0028.03 6.000-12.613 39.963 1.0020.30 5.465 -1.162 17.848 1.0034.15 11.035-16.416 36.570 1.00 16.42 6.472-14.869 -8.218 1.00 16.12 9.170 0.957 -2.297 1.0022.74 4.454 -4.651 10.416 1.00 20.60 20.460-25.521 7.764 1.00 26.25 7.681 -2.544 1.721 1.00 13.86 21.029-25.146 -8.372 1.00 17.33 14.028-12.601 28.828 1.00 15.39 25.022 -8.547 16.118 1.00 16.92 18.057 -3.215 49.932 1.0025.44 8.711 -22.401 12.910 1.0022.95 12.338 -7.514 37.880 1.0026.88 3.271-16.775 -4.316 1.00 19.56 0.541 0.196 50.275 1.0030.33 19.110-25.008 2.771 1.00 5.88 19.857 5.736-10.627 1.00 15.25 27.580-18.786 1.731 1.00 12.48 18.435 -0.552 -10.469 1.0026.95 14.333 -24.451 3.097 1.0021.65 15.425-11.850 25.550 1.00 19.62 7.024 -3.615 7.466 1.00 10.22 8.753 -20.576 29.006 1.0024.86 7.171 14.326 47.574 1.0038.64 27.936-19.870 -6.755 1.00 5.62 25.912-19.577 7.753 1.00 10.53 21.018 -23.427 -10.452 1.00 13.82 27.633 -1.667 12.559 1.00 16.07 4.313-13.120 12.150 1.0029.58 10.813 -25.473 .15.402 1.00 30.70 16.114 5.482 14.710 1.0033.54 18.745 -2.391 28.646 1.0029.04 11.904 1.212 24.223 1.0027.66 20.618 0.166 12.936 1.0013.20 2.553 2.198 49.034 1.0025.99 18.383 -9.766 -9.807 1.00 8.99 12.289 -2.356 38.708 1.00 18.95 28.530 -9.247 -6.290 1.00 15.87 7.140 2.348 42.142 1.0024.77 5.506 -6.185 1.158 1.0025.37 27.109 -2.182-10.612 1.00 35.24 23.698 -4.681 9.146 1.00 10.39 21.899 -8.055-10.315 1.00 19.23 9.190 21.320 27.616 1.0022.97 -1.064 9.065 47.775 1.00 17.17 23.562 -2.845 10.941 1.00 11.39 14.925 -18.028-13.375 1.00 38.75 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -208-

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199 1202 1205 1208 1211 1214 1217 1220 1223 1226 1229 t232 1235 1238 1241 1244 1247 1250 1253 1256 4259 4262 4265 4268 4271 4274 4277 4280 4283 4286 4289 4292 4295 4298 4301 4304 4307 4310 4313 4316 4319 4322 4325 4328 4331 4334 4337 4340 4343 4346 4349 4352 4355 4358 4361 4364 4367 4370 4373 437f 4379 4382 4385 4388 439 4394 439.

440( 440: 440< 440' 441: OH2 WAT W 80 OH2WATW 81 OH2 WAT W 82 OH2 WAT W 83 OH2 WAT W 84 OH2 WAT W 85 OH2 WAT W 86 OH2 WAT W 87 OH2 WAT W 88 OH2 WAT W 89 OH2 WAT W 90 OH2WATW 91 OH2 WAT W 92 OH2 WAT W 93 OH2 WAT W 94 OH2 WAT W 95 OH2 WAT W 96 OH2 WAT W 97 OH2 WAT W 98 OH2 WAT W 99 OH2 WAT W 100 OH2WATW 101 OH2 WAT W 102 OH2 WAT W 103 OH2 WAT W 104 OH2 WAT W 105 OH2 WAT W 106 OH2WATW 107 OH2 WAT W 108 OH2 WAT W 109 OH2 WATW 110 OH2 WAT W 111I OH2WATW 112 OH2WATW 113 OH2 WATW 114 OH2WATW 115 OH2WATW 116 OH2WATW 117 OH2WATW 118 OH2WATW 119 OH2 WAT W 120 OH2 WATW 121 OH2 WAT W 122 OH2 WAT W 123 OH2 WAT W 124 OH2WATW 125 OH2 WAT W 126 OH2 WAT W 127 OH2 WAT W 128 OH2 WAT W 129 OH2WATW 130 OH2WATW 131 OH2 WAT W 132 OH2WATW 133 OH2 WAT W 134 OH2WATW 135 OH2WATW 136 OH2 WAT W 137 SOH2WATW 138 OH2WATW 139 OH2WATW 140 SOH2WATW 141 SOH2WATW 142 i OH2WATW 143 1I OH2WATW 144 t OH2WATW 145 7 OH2 WAT W 146 OH2WATW 147 3 OH2 WAT W 148 5 OH2 WAT W 149 9 OH2WATW 150 2 OH2WATW 151 18.839-22.015 -1.607 1.00 16.43 6.261 9.572 3.405 1.00 10.35 8.820 -8.947 40.170 1.00 19.41 14.036 26.574 5.609 1.0030.50 14.876 15.952 -3.144 1.00 14.73 22.298-12.049-10.100 1.00 12.02 11.954-24.973 2.713 1.00 17.04 14.498-25.610 19.360 1.00 12.97 26.234 0.908 12.149 1.00 14.84 3.924 18.064 34.080 1.00 14.92 2.892-12.720 -0.149 1.0030.35 21.001 -0.118 -7.935 1.00 11.45 17.735 4.125 55.330 1.0023.03 30.909-19.022 0.239 1.00 18.12 8.234 0.633 -11.962 1.0035.87 -0.136 11.812 40.540 1.00 19.09 25.485 11.712 48.976 1.00 39.93 13.430 9.938 61.213 1.00 17.48 31.700 7.812 -5.575 1.00 19.58 15.210 0.308 35.919 1.00 11.83 -5.288-15.339 38.902 1.00 16.58 1.823 -1.479 48.170 1.0029.29 -10.016 4.695 47.612 1.0027.17 6.921 1.076 30.534 1.0021.69 20.055 0.656 43.920 1.0028.97 6.463 6.212 15.982 1.0021.65 13.122 23.767 -4.210 1.00 9.47 -9.026 -5.522 44.747 1.0032.78 29.646-16.411 0.821 1.0023.02 1.361 12.084 -0.538 1.0027.33 32.303 10.466 -1.708 1.00 22.13 28.782 -8.621 8.705 1.00 16.73 24.255 5.940-10.096 1.0017.97 13.049-12.039 26.267 1.00 17.02 23.675-12.526 16.932 1.00 18.85 28.157 2.239-10.357 1.0057.76 16.617-26.364 6.730 1.0014.43 25.797 11.257 9.549 1.0020.54 32.533 10.022 -4.580 1.0028.60 32.447 4.104 -6.869 1.0045.04 -11.651 12.202 46.743 1.00 24.53 2.087-13.590 -7.699 1.0034.84 5.697 -8.611 46.172 1.00 13.18 15.700 -9.174 24.055 1.0030.63 27.694-17.178 14.423 1.00 14.55 -17.440 6.655 48.327 1.0017.20 23.385-13.611 22.762 1.0026.67 17.644 1.422 26.967 1.0047.02 14.055 5.694 21.684 1.0023.91 -9.680 0.519 31.262 1.00 16.36 5.299 -6.710-15.375 1.0038.16 31.933 8.550 5.211 1.0013.75 14.320 -2.736 27.730 1.00 27.48 34.024 -3.394 1.152 1.0028.35 8.372 -8.434-11.747 1.00 16.01 21.336-24.763 25.455 1.00 21.80 38.405 7.861 2.254 1.00 18.43 7.136 11.670 49.549 1.0016.91 22.371 8.145 -1.106 1.00 3.60 -0.599 13.866 38.934 1.00 53.27 3.559 20.513 33.347 1.0025.23 26.012-21.730 3.659 1.00 8.89 16.747 19.742 12.697 1.00 12.58 22.905 1.078 -9.223 1.0033.61 13.909-25.966 12.927 1.00 18.24 -1.880-13.590 5.375 1.0022.46 31.991 -3.241 6.307 1.0021.74 4.296 -0.541 28.947 1.0026.69 21.118-26.880 23.879 1.00 16.34 21.937 7.882-11.795 1.0026.06 10.669-24.334 12.632 1.00 21.28 4.579 13.840 -6.207 1.00 7.70 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -209-

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4415 OH2WATW 152 4418 OH2WATW 153 4421 OH2WATW 154 4424 OH2WATW 155 4427 OH2WATW 156 4430 OH2WATW 157 4433 OH2WATW 158 4436 OH2 WAT W 159 4439 OH2 WAT W 160 4442 OH2WATW 161 4445 OH2 WAT W 162 4448 OH2WATW 163 4451 OH2WATW 164 4454 OH2 WAT W 165 4457 OH2 WAT W 166 4460 OH2 WAT W 167 4463 OH2 WAT W 168 4466 OH2 WAT W 169 4469 OH2 WAT W 170 4472 OH2WATW 171 4475 OH2WATW 172 4478 OH2WATW 173 4481 OH2WATW 174 4484 OH2WATW 175 4487 OH2 WAT W 176 4490 OH2 WAT W 177 4493 OH2WATW 178 4496 OH2 WAT W 179 4499 OH2 WAT W 180 4502 OH2WATW 181 4505 OH2 WAT W 182 4508 OH2 WAT W 183 4511 OH2WATW 184 4514 OH2WATW 185 4517 OH2WATW 186 4520 OH2WATW 187 4523 OH2WATW 188 4526 OH2WATW 189 4529 OH2WATW 190 4532 OH2WATW 191 4535 OH2 WAT W 192 4538 OH2WATW 193 4541 OH2WATW 194 4544 OH2WATW 195 4547 OH2 WAT W 196 4550 OH2WATW 197 4553 OH2WATW 198 4556 OH2WATW 199 4559 OH2 WAT W 200 4562 OH2WATW 201 4565 OH2WATW 202 4568 OH2 WAT W 203 4571 OH2WATW 204 4574 OH2 WAT W 205 4577 OH2 WAT W 206 4580 OH2 WAT W 207 4583 OH2 WAT W 208 4586 OH2 WAT W 209 4589 OH2WATW 210 4592 OH2WATW 211 4595 OH2WATW 212 4598 OH2WATW 213 4601 OH2WATW214 4604 OH2WATW 215 4607 OH2WATW 216 4610 OH2WATW217 4613 OH2WATW 218 4616 OH2WATW 219 4619 OH2WATW 220 4622 OH2 WAT W 221 4625 OH2 WAT W 222 4628 OH2 WAT W 223 30.211 6.160 11.009 1.00 16.94 24.991 -7.106 9.808 1.00 17.58 11.324 -3.831 36.762 1.00 23.50 -15.285 3.508 41.805 1.00 35.32 15.119 -24.580 -4.682 1.00 18.53 1.432 -5.537 7.573 1.0023.51 -11.941 17.134 41.007 1.00 30.42 6.869-18.832 28.614 1.00 19.33 12.995 -0.649 26.156 1.00 21.36 33.416 -5.676 6.213 1.0023.60 14.014 24.636 31.376 1.0036.78 1.227-14.938 26.127 1.0029.62 24.359 -8.407 -9.667 1.00 15.70 3.110 11.622 42.033 1.0020.46 10.688 22.835 -4.459 1.00 13.45 -6.717 -5.186 46.427 1.0031.64 5.512 -4.116 17.944 1.0032.66 -20.353 5.803 45.273 1.00 11.80 18.354 -6.705 -2.499 1.00 3.86 29.217-15.191 3.806 1.00 14.16 15.303 12.187 54.784 1.00 37.54 17.118-25.005 -9.465 1.0035.04 8.913 -1.469 19.169 1.0036.48 32.173 -8.909 4.706 1.00 19.69 28.509-17.036 -2.194 1.00 5.68 6.008 25.018 11.066 1.0022.81 20.228 3.127 40.490 1.0023.82 -0.663-13.682 40.615 1.0030.50 34.602 -2.615 5.839 1.0021.60 7.201 4.595 25.466 1.00 15.09 -4.692 11.606 31.073 1.0020.86 21.437-23.456 9.533 1.0031.82 13.849 17.698 46.008 1.0021.96 17.169 -16.870 -12.443 1.00 20.68 19.737 -21.287 -14.670 1.0027.48 12.044 14.653 15.347 1.00 19.96 5.432 -6.588 -12.779 1.0035.66 4.591 13.681 39.908 1.0020.33 21.602 5.346 41.670 1.0036.13 29.191-21.778 7.396 1.0020.15 18.030 -9.969 24.699 1.0036.15 12.481 -28.048 4.388 1.00 18.19 12.908 10.097 21.791 1.0038.97 25.645 8.682 49.741 1.0027.52 24.782 10.751 46.034 1.00 10.14 28.043 -17.199 -7.803 1.0047.72 26.889 3.775 48.529 1.0027.25 15.947 0.435 -1.489 1.00 13.61 5.673 -3.788 25.327 1.0030.04 23.387 6.262 13.666 1.00 11.98 4.263 5.267 17.454 1.0021.77 0.248 -9.252 42.163 1.00 15.59 25.046 2.931 -8.777 1.00 19.57 20.186 1.205 -9.775 1.0034.32 -3.206 8.912 32.847 1.00 6.08 16.094-17.057 -8.819 1.0022.31 19.191 8.829-10.872 1.0042.96 1.679 -6.926 45.370 1.0037.43 -8.601 4.482 49.821 1.0025.82 3.765 -7.431 27.914 1.0027.19 23.683 -2.641 -13.590 1.00 28.44 29.132 12.371 -6.415 1.0038.04 23.909-20.852 2.386 1.00 5.04 27.253 3.777 37.228 1.0024.05 5.162-12.163 14.867 1.0013.79 7.513 3.997 14.327 1.0026.14 20.390 10.391 8.341 1.00 2.00 17.322 -1.860 -8.500 1.00 18.45 6.864 18.400 -1.951 1.00 18.17 30.509-17.379 -8.974 1.00 9.31 1.1I15 -13.852 28.538 1.00 22.20 4.674 4.615 24.939 1.00 14.99 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -210-

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4631 4634 4637 4640 4643 4646 4649 4652 4655 4658 4661 4664 4667 4670 4673 4676 4679 4682 4685 4688 4691 4694 4697 4700 4703 4706 4709 4712 4715 4718 4721 4724 4727 4730 4733 4736 4739 4742 4745 4748 4751 4754 4757 4760 4763 4766 4769 4772 4775 4778 4781 4784 4787 4790 4793 4796 4799 4802 4805 4808 4811 4814 4817 4820 4823 4826 4829 4832 4835 4838 4841 4844 OH2 WAT W 224 OH2 WAT W 225 OH2 WAT W 226 OH2 WAT W 227 OH2 WAT W 228 OH2 WAT W 229 OH2 WAT W 230 OH2 WAT W 231 OH2 WAT W 232 OH2 WAT W 233 OH2 WAT W 234 OH2 WAT W 235 OH2 WAT W 236 OH2 WAT W 237 OH2 WAT W 238 OH2 WAT W 239 OH2 WAT W 240 OH2 WAT W 241 OH2 WAT W 242 OH2 WAT W 243 OH2 WAT W 244 OH2 WAT W 245 OH2 WAT W 246 OH2 WAT W 247 OH2 WAT W 248 OH2 WAT W 249 OH2 WAT W 250 OH2 WAT W 251 OH2 WAT W 252 OH2 WAT W 253 OH2 WAT W 254 OH2 WAT W 255 OH2 WAT W 256 OH2 WAT W 257 OH2 WAT W 258 OH2 WAT W 259 OH2 WAT W 260 OH2 WAT W 261 OH2 WAT W 262 OH2 WAT W 263 OH2 WAT W 264 OH2 WAT W 265 OH2 WAT W 266 OH2 WAT W 267 OH2 WAT W 268 OH2 WAT W 269 OH2 WAT W 270 OH2 WAT W 271 OH2 WAT W 272 OH2 WAT W 273 OH2 WAT W 274 OH2 WAT W 275 OH2 WAT W 276 OH2 WAT W 277 OH2 WAT W 278 OH2 WAT W 279 OH2 WAT W 280 OH2 WAT W 281 OH2 WAT W 282 OH2 WAT W 283 OH2 WAT W 284 OH2 WAT W 285 OH2 WAT W 286 OH2 WAT W 287 OH2 WAT W 288 OH2 WAT W 289 OH2 WAT W 290 OH2 WAT W 291 OH2 WAT W 292 OH2 WAT W 293 OH2 WAT W 294 OH2 WAT W 295 0.142 17.456 18.372 1.0024.15 9.859-27.543 -4.527 1.0024.23 17.960 7.797 29.085 1.0026.71 26.317 5.155 -2.166 1.00 7.58 16.430 -0.855 25.960 1.00 51.29 8.210-11.591 39.186 1.0024.13 -0.777 11.927 32.428 1.0014.96 10.186 -6.629 43.558 1.0027.57 0.958 9.102 32.585 1.0024.54 2.553 11.712 32.867 1.0021.65 6.680 -0.006 43.521 1.0010.20 18.239-24.609 5.252 1.00 11.95 8.204 6.152 12.418 1.0021.41 23.369 13.641 49.711 1.0030.08 17.028 -7.732 -4.387 1.0015.78 30.807-10.059 6.565 1.0027.21 -6.711 -6.520 32.290 1.0029.81 16.555-12.917 28.106 1.0036.06 12.165-24.551 -7.873 1.00 19.39 21.126 12.813 35.206 1.0024.60 18.219 -8.460 20.415 1.0023.62 20.193 10.009 34.435 1.0011.86 29.732 9.455 -8.377 1.0034.43 13.170 2.121 14.946 1.0024.74 23.497-25.395 4.299 1.00 13.44 14.041 -22.771 -6.627 1.00 17.30 10.311 0.550 16.295 1.0041.70 13.522 2.361 -9.507 1.0020.28 13.590-26.409 -3.831 1.00 15.20 24.905 10.098 -7.007 1.0029.35 13.023 -15.944 -13.638 1.00 26.25 -15.059 5.616 39.922 1.0039.38 16.372 15.953 31.052 1.00 19.01 12.577 -9.193 43.694 1.0020.05 13.243 -8.179 23.993 1.0041.00 14.788 0.546-10.706 1.0028.58 19.882 -1.770-13.479 1.0035.11 31.349-15.664 -0.850 1.0026.24 14.405-13.078-16.126 1.00 16.37 22.733 13.041 16.231 1.0021.47 16.542 21.606 39.036 1.0026.03 -6.590 -9.660 42.823 1.0026.79 32.784 6.735 -7.882 1.0026.76 7.826 14.049 16.469 1.00 18.53 35.586 1.152 10.429 1.0031.99 13.273 -7.774 41.272 1.0027.81 26.613 -16.200 -10.311 1.0024.35 9.380 21.735 36.262 1.0026.21 2.143 -1.862 26.631 1.0019.18 4.996-16.490 24.247 1.00 21.38 -3.681 11.524 26.326 1.00 32.16 -0.488 20.208 19.551 1.0028.61 20.222 13.839 -1.397 1.00 6.13 7.951 8.338 14.092 1.0026.36 -0.102 -4.099 27.252 1.0022.58 6.465-12.539 22.787 1.00 39.32 27.940 -9.420 11.870 1.0021.31 18.053 -5.607 47.195 1.0028.13 27.663-20.337 5.833 1.0029.05 7.299 3.352 5.485 1.00 15.35 -1.957 14.568 1.632 1.0030.36 11.592 -3.121 17.799 1.0019.72 21.824-21.684 1.192 1.0014.10 21.037 -6.590 -2.851 1.0010.76 15.218 0.054 17.590 1.0023.02 17.319 -6.704 54.240 1.00 23.81 22.151-16.769 24.819 1.0026.10 11.461 -1.517-14.214 1.00 17.37 9.524 1.115 23.430 1.0018.75 13.384 17.543 21.896 1.0032.59 26.874 -7.117 7.979 1.00 19.34 21.770-13.114-13.708 1.0029.49 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -211-

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4847 4850 4853 4856 4859 4862 4865 4868 4871 4874 4877 4880 4883 4886 4889 4892 4895 4898 4901 4904 4907 4910 4913 4916 4919 4922 4925 4928 4931 4934 4937 4940 4943 4946 4949 4952 OH2 WAT W 29 OH2 WAT W 29 OH2 WAT W 29 OH2 WAT W 29 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 30 OH2 WAT W 3 OH2 WAT W 31 OH2 WAT W 3 OH2 WAT W 31 OH2 WAT W 31 OH2 WAT W 31 OH2 WAT W 3 OH2 WAT W 31 OH2 WAT W 31 OH2 WAT W 31 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 33 OH2 WAT W 33 '6 11.447 -7.221 35.170 1.00 22.34 '7 18.712 0.549 -7.664 1.00 16.39 '8 -15.915 3.391 44.805 1.00 37.24 '9 8.370 -8.297 42.696 1.0028.38 10 2.495 -9.286 23.003 1.00 35.16 I1 22.017 -7.975 -0.795 1.00 6.11 12 21.946-24.501 2.086 1.00 8.66 13 20.054-25.320 17.657 1.00 9.01 14 16.993 -22.098 5.024 1.00 5.97 5 5.968 -7.519 14.076 1.0041.33 6 32.836-13.233 -1.523 1.00 7.51 17 -7.127 13.283 28.100 1.00 26.60 18 6.091 -19.633 20.653 1.00 34.63 19 5.315 8.969 12.397 1.00 19.78 0 12.008 2.607 52.956 1.00 21.69 I 10.006 19.903 41.503 1.00 33.05 2 13.090 -23.821 -10.159 1.00 36.76 3 8.580-24.171 7.883 1.0034.91 4 29.016 -9.885 -3.451 1.0029.41 5 14.762 -9.284 46.366 1.00 40.86 6 7.236 26.011 3.913 1.0028.36 7 24.009 5.886 39.309 1.00 21.45 8 8.878 7.302 16.729 1.0036.71 9 -1.085 -7.737 23.652 1.00 40.27 20 22.737 3.022 44.290 1.00 31.90 21 11.113 -9.661 22.079 1.0038.45 2 22.328 0.316-12.103 1.0023.98 23 6.697 14.352 -9.527 1.0045.55 24 -8.008 -4.161 27.922 1.00 29.83 25 1.400 17.962 34.791 1.00 30.61 26 19.807 10.037 25.470 1.00 33.30 27 2.104 14.448 12.247 1.0037.11 28 15.269 -4.273 25.237 1.00 29.17 29 12.997 28.118 24.336 1.00 30.90 30 1.930 -6.058 27.027 1.00 18.90 31 20.207 17.499 33.744 1.00 41.90 -3.670 11.897 28.662 1.00 34.52 7.058 -2.556 18.576 1.00 56.55 -18.942 6.315 46.932 1.00 25.08 31.184-13.965 -2.378 1.00 17.70 7.095 -7.647 -14.341 1.00 57.21 9.338 21.684 24.997 0.75 48.85 22.060 5.827 -10.270 0.75 26.79 17.857 -0.598 27.682 0.75 56.40 -19.060 3.947 48.046 1.00 22.14 30.936-12.255 -4.119 1.0026.88 4955 CD 4956 CD 4957 CD 4958 CD 4959 CD 4960 CD 4961 CD 4962 CD 4963 CL 4964 CL HET I HET I HET I HET I HET I HET I HET I HET I CHL I CHL I SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -212- Table 2b

CRYSTI

SCALE 1 SCALE2 SCALE3

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42.196 83.729 67.237 90.00 93.30 90.00 P21 0.023699 0.000000 0.001366 0.00000 0.000000 0.011943 0.000000 0.00000 0.000000 0.000000 0.014897 0.00000 CB ILE L 3 CG2 ILE L 3 CGI ILEL 3 CD ILE L 3 C ILEL 3 O ILEL 3 N ILEL 3 CA ILE L 3 SN VALL 4 CA VAL L 4 SCB VAL L 4 SCGIVALL 4 SCG2 VAL L 4 C VALL 4 O0 VALL 4 I N VALL 5 CA VAL L 5 1 CB VAL L 5 1 CGI VALL 5 i CG2 VALL 5 iC VALL 5 0 OVALL 5 SN THRL 6 CA THR L 6 1 CB THR L 6 SOGI THRL t CG2 THR L 5 C THRL 6 5 O THRL 6 7 N GLN L 7 CA GLN L 7 0 CB GLN L 7 1 CG GLN L 7 2 CD GLN L 7 3 OE1 GLN L 4 NE2GLNL 7 C GLN L 7 8 0 GLNL 7 9 N GLU L 8 1 CA GLU L 2 CB GLU L E 3 CG GLU L 4 CD GLU L 5 OEl GLU L 6 OE2 GLU L 7 C GLUL 8 :8 O GLUL 8 ;9 N SERL 9 ii CA SERL 9 i2 CB SER L 9 31.905 -1.198 8.770 1.0022.21 30.889 -2.301 8.558 1.0027.45 31.377 0.099 8.176 1.0024.21 32.325 1.259 8.206 1.0025.48 30.908 -0.419 10.822 1.0021.44 29.898 -1.093 10.998 1.0020.56 32.310 -2.410 10.862 1.0020.99 32.131 -1.068 10.239 1.0021.17 31.004 0.881 11.110 1.0020.05 29.901 1.600 11.728 1.0020.43 30.358 2.220 13.042 1.00 17.54 29.161 2.832 13.761 1.00 19.60 31.020 1.155 13.907 1.00 17.28 29.350 2.705 10.834 1.0020.60 30.091 3.599 10.429 1.0020.97 28.037 2.646 10.593 1.0020.30 27.341 3.599 9.739 1.00 17.97 26.378 2.823 8.824 1.0017.56 25.504 3.752 7.989 1.00 16.02 27.188 1.881 7.940 1.00 17.98 26.565 4.566 10.620 1.0018.99 25.672 4.143 11.342 1.0018.18 26.898 5.849 10.560 1.0017.10 26.267 6.854 11.460 1.00 16.73 27.374 7.687 12.137 1.00 15.12 6 28.157 6.832 12.966 1.00 17.77 S26.816 8.801 12.988 1.0020.38 25.290 7.797 10.746 1.00 15.26 25.573 8.275 9.635 1.00 14.60 24.135 8 23.121 21.856 22.020 20.712 20.484 19.805 22.787 9 23.200 22.072 1 21.644 21.124 22.179 22.261 21.670 22.936 20.520 1 19.634 1 20.478 1 19.438 19.742 .069 9.003 8.252 7.230 6.612 5.46 7.371 .986 ).764 1.070 11.409 1.00 14.21 10.914 1.00 9.76 10.519 1.00 8.55 9.405 1.00 3.66 9.060 1.00 4.16 1 9.343 1.00 10.06 8 8.473 1.00 2.55 12.037 13.175 11.713 1.00 12.95 1.00 12.95 1.00 14.59 12.044 13.317 14.142 13.874 12.870 14.667 1.439 10.812 1.677 1 11.043 11.078 12.720 1.00 9.44 12.081 1.00 3.83 11.390 1.00 8.12 9.885 1.00 12.60 9.432 1.00 8.76 9.156 1.00 12.58 13.522 12.954 4.833 15.608 17.117 1.00 9.97 1.00 10.41 1.00 11.56 1.00 8.58 1.00 14.23 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -2 13-

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OG SER L 9 C SER L 9 0 SER L 9 N ALA L 10 CA ALA L 10 CB ALA L 10 C ALA L 10 0 ALA L 10 N LEU L I1I CA LEU L I11 CB LEU L I11 CG LEU L I11 CDI LEU L I1I CD2 LEU L I11 C LEUL 11 O LEUL 11 N THR L 12 CA THR L 12 CB TI-R L 12 OG ITHR L 12 CG2 THR L 12 C THR L 12 0 THR L 12 N THR L 13 CA THR L 13 CB THR L 13 OG ITHR L 13 CG2 THR L 13 C THR L 13 O THR L 13 PN SER L 14 *CA SER L 14 CB SER L 14 OG SER L 14 C SER L 14 0 SER L 14 1N PRO L 15 20.274 12.318 17.522 1.00 21.30 18.090 11.570 15.330 1.00 7.24 17.164 10.799 15.246 1.00 6.90 17.922 12.864 15.189 1.00 6.82 16.587 13.364 14.882 1.00 6.68 15.774 13.542 16.158 1.00 9.20 16.692 14.689 14.233 1.00 6.99 17.644 15.397 14.502 1.00 8.81 15.711 15.033 13.431 1.00 7.46 15.669 16.344 12.794 1.00 6.63 16.167 16.277 11.323 1.00 10.52 17.504 15.576 11.023 1.00 10.17 17.757 15.548 9.520 1.00 8.53 18.639 16.275 11.718 1.00 7.59 14.217 16.796 12.773 1.00 5.60 13.341 15.965 12.677 1.00 7.61 13.973 18.114 12.826 1.00 4.15 12.609 18.685 12.814 1.00 6.68 12.361 19.471 14.143 1.00 10.20 12.509 18.579 15.267 1.00 10.18 10.975 20.098 14.149 1.00 4.50 12.461 19.702 11.663 1.00 9.42 13.361 20.537 11.422 1.00 11.76 11.347 19.705 11.003 1.00 12.34 11.179 20.647 9.945 1.00 13.42 11.707 20.011 8.610 1.00 15.26 11.997 21.027 7.647 1.00 19.73 10.696 19.059 8.027 1.00 15.31 9.719 21.052 9.816 1.00 13.88 8.787 20.272 10.151 1.00 12.15 9.479 22.283 8.124 22.660 7.950 24.194 8.798 24.824 7.802 22.100 8.697 21.878 6.561 21.792 5.423 21.907 6.202 21.253 4.703 20.978 4.267 21.855 6.559 22.283 6.623 23.473 6.852 21.807 9.368 1.00 8.75 9.114 1.00 10.75 9.110 1.00 15.90 10.110 1.00 21.10 7.778 1.00 10.99 6.976 1.00 10.06 7.514 1.00 11.57 8.418 1.00 11.51 6.217 1.00 13.73 6.340 1.00 12.67 7.461 1.00 13.25 5.121 1.00 15.44 5.418 1.00 14.98 3.898 1.00 12.73 CD PRO L 15 CA PRO L 15 GB PRO L 15 CG PRO L 15 C PRO L 15 O PRO L 15 N GLY L 16 CA GLY L 16 C GLY L 16 O GLY L 16 N GLU L 17 CA GLU L 17 GB GLU L 17 CG GLU L 17 CD GLU L 17 OEI GLU L 17 OE2 GLU L 17 C GLU L 17 O GLU L 17 7.189 22.698 2.804 1.00 11.86 8.654 23.047 2.741 1.00 11.99 9.108 23.638 1.781 1.00 16.69 9.412 22.738 3.747 1.00 10.28 10.807 23.015 3.671 1.00 8.33 11.328 23.510 5.013 1.00 6.44 10.669 24.816 5.440 1.00 11.47 10.780 25.884 4.351 1.00 5.30 11.953 26.232 3.965 1.00 6.09 9.701 26.346 3.902 1.00 7.10 11.560 2 1.779 3.226 1.00 8.34 11.006 20.676 3.238 1.00 10.48 SUBSTITUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 .2 14-

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N THR L 18 GA THR L 18 GB THR L 18 OG ITHR L 18 GG2 THR L 18 C THR L 18 0 THR L 18 N VAL L 19 GA VAL L 19 GB VAL L 19 CGGIVAL L 19 CG2 VAL L 19 C VAL L 19 0 VAL L 19 N T-R L 20 GA THR L 20 GB THR L 20 OG ITHR L 20 CG2 THR L 20 C THR L20 O THR L20 N LEU L21 CA LEU L 21 GB LEU L 21 CG LEU L 21 CD] LEU L 21 GD2 LEU L 21 C LEUL 21 O LEU L21 N THR L22 GA THR L 22 GB THR L 22 001 THR L 22 GG2 THR L 22 C THR L22 0 THR L22 N GYS L23 GA CYS L 23 GB CYS L 23 SG GYS L 23 G CYS L23 O GYS L23 N ARG L24 GA ARG L 24 GB ARG L 24 GG ARG L 24 GD ARO L 24 NE ARG L 24 CZ ARG L 24 12.825 21.968 2.878 1.00 7.25 13.676 20.874 2.418 1.00 6.74 14.569 21.384 1.242 1.00 3.14 13.715 21.629 0.088 1.00 2.24 15.708 20.416 0.919 1.00 5.50 14.579 20.429 3.555 1.00 5.28 15.121 21.267 4.286 1.00 4.15 14.815 19.129 3.652 1.00 5.05 15.714 18.598 4.666 1.00 6.85 14.949 17.763 5.781 1.00 8.11 14.478 18.604 6.951 1.00 12.22 13.748 17.040 5.167 1.00 11.25 16.693 17.624 4.009 1.00 7.00 16.323 16.880 3.113 1.00 8.38 17.894 17.605 4.503 1.00 7.91 18.852 16.632 4.094 1.00 10.04 20.042 17.279 3.312 1.00 8.38 19.537 17.742 2.053 1.00 10.18 21.179 16.295 3.071 1.00 7.29 19.360 15.859 5.320 1.00 10.78 19.729 16.451 6.353 1.00 14.77 19.296 14.530 5.192 1.00 8.97 19.814 13.586 6.162 1.00 5.71 18.807 12.431 6.310 1.00 7.30 17.445 12.710 6.929 1.00 3.52 16.597 13.551 5.999 1.00 12.30 16.737 11.422 7.224 1.00 5.61 21.092 13.017 5.599 1.00 5.00 21.132 12.728 4.388 1.00 6.66 22.136 12.830 6.414 1.00 4.47 23.353 12.205 5.913 1.00 8.68 24.584 13.092 6.055 1.00 8.60 24,895 13.288 7.446 1.00 13.20 24.361 14.408 5.365 1.00 12.92 23.656 1 23.039 1 24.623 1 24.969 24.119 24.572 26.443 26.903 27.2 16 28.65 1 29.459 29. 196 30.230 31.602 32.571 0.8 17 0.375 0.165 8.822 7.903 6.174 8.613 8.673 8.399 8.235 9.273 9.359 10.25 9.792 10.61 6.538 1.00 12.45 7.556 1.00 12.78 5.949 1.00 9.70 6.322 1.00 12.79 5.457 1.00 11.70 5.429 1.00 14.38 6.089 1.00 11.83 4.959 1.00 13.63 7.154 1.00 13.74 6.975 1.00 15.34 7.740 1.00 17.58 9.212 1.0023.61 1 9.878 1.00 27.66 9.607 1.00 30.74 1 9.199 0.01 28.45 NH1 ARO L 24 NH2 ARO L 24 G ARG L24 0 AR L 24 N SER L25 CA SER L 25 GB SER L 25 33.788 10.139 32.325 11.905 29.134 6.869 7 28.469 6.140 8 30.284 6.522 6.

30.913 5.239 31.289 4.6035 8.972 0.01 28.77 9.015 0.01 27.96 .335 1.00 16.36 .083 1.00 15.58 765 1.00 14.90 .014 1.00 15.33 .681 1.00 20.16 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -2

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202 204 205 206 208 209 210 212 213 214 216 217 218 220 221 222 223 225 226 227 228 230 231 232 233 234 236 237 238 239 240 241 242 244 245 246 248 249 250 251 253 254 255 257 258 259 260 262 263 264 266 267 268 270 OG SER L 25 C SER L25 O SER L25 N SER L26 GA SER L 26 GB SER L 26 OG SER L 26 C SER L26 O SER L26 N THR L27 GA THR L 27 GB THR L 27 OGI THR L 27 CG2 THR L 27 C THR L27 0 THR L27 N GLY L27A CA GLY L 27A C GLY L27A O GLY L 27A N ALA L27B CA ALA L 27B GB ALA L 27B C ALA L27B 0 ALA L27B N VAL L27C CA VAL L 27C GB VAL L 27G CG I VAL L 27C CG2 VAL L 27C C VAL L27G O VAL L 27G N THR L28 GA THR L 28 GB THR L 28 OGI THRL 28 GG2 THR L 28 G T-R L 28 0 THR L28 N THR L29 GA THR L 29 GB TH-R L 29 OGI THRL 29 GG2 THR L 29 G THR L29 0 THR L29 N SER L 30 GA SER L 30 GB SER L 30 OG SER L 30 G SER L30 0 SERL 30 N ASN L31 GA ASN L 31 3 3 32.145 3.490 5.853 1.00 23.32 12.156 32.869 32.385 33.552 33.376 33.203 14.856 35.939 34.761I 5.467 6.421I 4.6 16 4.747 3.841 2.482 4.349 4.489 3.836 7.879 1.00 14.75 7.673 1.00 16.11 8.864 1.00 15.20 9.736 1.00 19.00 10.960 1.00 16.96 10.552 1.00 19.34 9.012 1.00 19.93 9.559 1.00 23.14 7.800 1.00 20.53 7.128 1.00 19.87 6.411 1.00 21.22 35.952 3.358 35.633 2.079 34.457 2.255 5.626 1.00 24.06 35.388 0.990 7.430 1.00 23.05 36.520 4.385 6.163 1.00 19.65 37.711 4.370 5.825 1.00 20.98 35.672 5.287 5.72 1 1.00 20.47 36.115 6.334 4.835 1.00 15.37 34.954 6.903 4.102 1.00 14.56 33.832 6.766 4.539 1.00 16.44 35.225 7.549 2.975 1.00 14.44 34.181 8.166 2.158 1.00 13.84 34.819 8.849 0.926 1.00 10.44 33.160 7.161 1.671 1.00 14.20 33.5 16 6.038 1.285 1.00 16.84 31.911 7.559 1.666 1.00 12.61 30.898 6.761 1.026 1.00 14.17 29.531 7.067 1.621 1.00 13.42 28.472 6.199 0.983 1.00 14.92 29.592 6.824 3.116 1.00 14.29 30.907 7.097 -0.478 1.00 16.22 30.841 8.282 -0.851 1.00 16.42 3 1.067 6.061 -1.325 1.00 15.73 3 1.082 6.232 -2.803 1.00 14.38 32.401 5.745 -3.445 1.00 12.94 32.448 4.336 -3.415 1.00 13.65 33.606 6.278 -2.713 1.00 11.90 29.940 5.448 -3.447 1.00 12.92 29.134 4.821 -2.760 1.00 9.64 29.859 5.480 -4.763 1.00 12.65 28.776 4.795 -5.453 1.00 14.40 28.778 5.093 -6.972 1.00 15.28 30.119 4.879 -7.479 1.00 16.73 28.322 6.530 -7.249 1.00 16.74 28.891 27.922 30.066 30.284 3 1.769 32.359 29.621 29.584 3.296 -5.273 2.566 -5.455 2.849 -4.912 1.440 -4.697 1.177 -4.630 1.484 -5.874 0.945 -3.416 -0.237 -3.168 1.00 14.04 1.00 17.19 1.00 14.83 1.00 16.69 1.00 18.52 1.00 22.73 1.00 18.22 1.00 17.69 29.127 1.846 -2.590 1.00 16.05 28.449 1.434 -1.355 1,00 12.29 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCTIGB98/02542 -216-

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CB ASN L 31 CG ASN L 31 ODI ASN L 31 ND2 ASN L 31 C ASN L31 O ASNL 31 N TYR L32 CA TYR L 32 CB TYR L 32 CG TYR L 32 CD I TYR L 32 CEI TYR L 32 CD2 TYR L 32 CE2 TYR L 32 CZ TYR L 32 OH TYR L 32 C TYR L32 O TYR L32 N ALA L33 CA ALA L 33 CB ALA L 33 C ALA L33 O ALA L33 N ASN L34 CA ASN L 34 GB ASN L 34 CG ASN L 34 ODI ASN L 34 ND2 ASN L 34 C ASN L34 0 ASN L34 N TRP L 35 CA TRP L 35 GB TRP L 35 CG TRP L 35 CD2 TRPL 35 CE2 TRP L 35 CE3 TRP L 35 CDI TRP L 35 NEI TRP L 35 CZ2 TRP L 35 CZ3 TRP L 35 CH2 TRP L 35 C TRP L35 O TRP L35 N VAL L36 CA VAL L 36 GB VAL L 36 CGI VAL L 36 CG2 VAL L 36 C VAL L36 O VAL L36 N GLN L37 CA GLN L 37 GB GLN L 37 CG GLN L 37 28.704 30.112 30.84 30.52: 26.972 26.222 26.555 25. 160 24.818 25.710 27.01( 27.859 25.28: 26.131 27.425 28.323 24.203 23.269 24.408 23.576 23.873 22.086 21.603 2 1.357 19.892 19.358 19.466 7 2.472 -0.271I 2.426 0.212 3.384 0.091 1.324 0.761 1.00 9.73 1.00 5.99 1.00 9.76 1.00 3.79 1.276 0.938 1.527 1.473 0.076 -0.373 -0.834 -1.19" -0.314 -0.68( -1.580 -0.658 -2.830 -3.2 17 -3.775 -4.931 0 -4.68 -5.71 0 -6.26 -7.32~ 1.00 10.21 1.00 9.59 1.00 8.64 1.00 7.71 1.00 11.29 1.00 11.41 8 1.00 14.39 6 1.00 14.44 2 1.00 17.67 9 1.00 11.36 1. 114 -7.045 1.00 17.13 -1.410 -8.087 1.00 21.48 1.855 2.063 1.00 11.23 1.105 -1.741 1.00 6.50 3.053 -1.461 1.00 11.42 3.476 -0.310. 1.00.-14.19 4.918 0.090 1.00 10.80 3.359 -0.549 1.00 10.34 3.857 -1.555 1.00 8.45 2.711 0.404 1.00 7.12 2.659 0.373 1.00 5.84 1.247 0.571 1.00 3.46 0.414 -0.680 1.00 7.07 18.468 -0.071 -1.209 1.00 5.20 20.684 0.244 -1.154 1.00 5.40 19.299 19.956 18.064 17.332 17. 171 18.477 19.085 20.339 18.678 19.367 20.473 21.221 19.551 20.8 10 3.525 3.794 3.959 4.692 6.2 16 6.997 7.645 8.113 7.870 7.124 7.778 8.799 8.549 9.005 1.459 1.00 5.10 2.431 1.00 6.58 1.259 1.00 5.01 2.283 1.00 6.70 1.946 1.00 7.73 1.949 1.00 7.11 3.093 1.00 8.09 2.703 1.00 5.38 4.430 1.00 10.50 0.911 1.00 4.99 1.362 1.00 6.98 3.589 1.00 5.76 5.297 1.00 6.19 4.874 1.00 3.95 16.000 4.031 2.417 1.00 6.29 15.325 3.778 1.405 1.00 6.53 15.672 3.703 14.478 2.972 14.813 1.554 13.506 0.851 15.564 0.684 13.691 3.768 14.248 4.303 12.399 3.809 11.519 4.533 10.525 5.309 9.741 6.290 3.666 4.04 5 4.655 5.08 3.61' 5.084 6.022 4.899 5.779 4.957 5.782 1.00 5.99 1.00 5.23 1.00 6.23 S1.00 2.37 t 1.00 3.99 1.00 4.86 1.00 7.07 1.00 5.26 1.00 10.98 1.00 10.61 1.00 10.14 SUBSTiTUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -2 17-

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339 CD GLN L 37 340 OEI GLN L 37 341 NE2 GLN L 37 .344 C GLN L37 345 0 GLN L37 346 N GLU L38 348 CA GLU L 38 349 GB3 GLU L 38 350 CG GLU L 38 351 CD GLU L 38 352 OEI GLU L 38 353 0E2 GLU L 38 354 C GLU L38 355 0 GLU L38 356 N LYS L 39 358 CA LYS L 39 359 GB LYS L 39 360 CG LYS L 39 361 CD LYS L 39 362 CE LYS L 39 363 NZ LYS L 39 367 C LYS L 39 368 0 LYS L 39 369 N PROL 40 370 CD PRO L 40 371 CA PRO L 40 372 C1B PRO L 40 373 CG PRO L 40 374 C PRO L40 375 0 PRO L 40 376 N ALAL 41 378 CA ALA L 41 379 GB ALA L 41 380 C ALA L41 381 0 ALA L41 382 N HIS L 42 384 CA HIS L 42 385 GB3 HIS L 42 386 CG HIS L 42 387 CD2 HIS L 42 388 NDI HIS L 42 390 GEl HIS L 42 391 NE2 HIS L 42 393 C HIS L 42 394 0 HIS L 42 395 N LEU L43 397 CA LEU L 43 398 GB3 LEU L 43 399 CG LEU L 43 400 CDI LEU L 43 401 CD2 LEU L 43 402 C LEU L43 403 0 LEU L43 404 N PHE L44 406 CA PHE L 44 407 GB PHE L 44 8.607 7.788 8.549 10.722 10.126 10.675 9.853 10.677 9.839 10.6 18 11.747 10.08 1 8.713 4 8.958 5 7.484 3 6.358 5.348 5.777 4.645 5.167 4.104 5.728 3.

5.778 2 5.134 4 4.954 4.505 3.5434 3.563 3.804 2 2.930 2 4.290 1 3.831 2.435 6.827 6.066 8.139 3.6 14 2.656 3.956 3.223 2.724 1.948 1.491 1.90 0.694 .100 .094 .742 4.424 t.743 5.942 6.445 .426 7.9 12 4.999 1.00 15.44 4.504 1.00 18.50 4.859 1.00 15.77 6.683 1.00 11.84 6.211 1.00 15.29 7.976 1.00 13.42 8.919 1.00 12.58 10.118 1.00 12.59 11.160 1.00 11.75 12.372 1.00 9.26 12.546 1.00 12.30 I13.157 1.00 17.41 9.455 1.00 14.00 10.163 1.00 12.02 9.126 1.00 13.36 9.695 1.00 15.90 8.626 1.00 14.39 7.806 1.00 15.78 6.935 1.0022.14 5.888 1.00 25.73 4.945 1.00 27.82 .607 10.852 1.00 20.86 .341 10.896 1.00 18.39 .308 11.828 1.0025.47 5.763 11.895 1.00 28.62 3.681 12.975 1.00 28.32 4.770 13.526 1.0028.73 5.834 12.480 1.00 30.27 .365 12.6 16 1.00 28.70 .301 11.709 1.0025.53 .328 13.333 1.00 30.46 .0.059 13.244 1.00 28.13 .0.174 12.622 1.00 29.92 4.819 -0.905 12.481 4.434 -1.889 11.871 6.101 -0.531 12.505 7.107 7.123 7.624 6.999 8.94 5 9.186 8.025 -1.346 -2.746 -2.73 8 -2.731 -2.550 -2.4 12 -2.5 19 11.839 12.437 13 .806 15.01: 14.06 15.347 15.92~ 1.00 24.45 1.00 26.51 1.00 22.07 1.00 20.06 1.00 20.43 1.00 17.71 3 1.00 17.56 8 1.0021.55 1.00 19.46 91.00 17.49 6.823 -1.474 10.366 1.0021.88 6.999 -2.549 9.799 1.00 22.22 6.326 -0.408 9.750 1.00 20.03 6.057 -0.452 8.337 1.00 20.01 4.844 0.394 8.018 1.00 24.58 3.587 0.058 8.828 1.00 27.32 2.565 1.181 8.678 1.00 26.38 3.027 -1.328 8.423 1.00 24.37 7.264 0.087 7.623 1.00 18.27 7.576 1.266 7.750 1.00 18.64 7.966 -0.785 6.919 1.00 17.14 9.184 -0.395 6.237 1.00 13.89 10.265 -1.388 6.547 1.00 10.76 SUBSTITUTE SHEET (RULE 2B) WO 99/10379 PCT/GB98/02542 -218-

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408 409 410 411 412 413 414 415 416 418 419 420 422 423 424 425 427 428 429 430 432 433 434 435 436 437 438 439 441 442 443 444 445 446 447 448 450 451 452 453 455 456 457 458 460 461 462 464 465 466 467 469 470 471 472 473 CG PHE L 44 CDI PHE L 44 CD2 PHE L 44 CEI PHE L 44 CE2 PHE L 44 CZ PHE L 44 C PHE L 44 O PHE L 44 N THR L 45 CA THR L 45 CB THR L 45 OG1 THRL 45 CG2 THR L 45 C THR L 45 O THRL 45 N GLY L 46 CA GLY L 46 C GLY L 46 O GLY L 46 N LEU L 47 CA LEU L 47 CB LEU L 47 CG LEU L 47 CDI LEU L 47 CD2 LEU L 47 C LEU L 47 O LEU L 47 N ILE L 48 CA ILE L 48 CB ILE L 48 CG2 ILE L 48 CGI ILE L 48 CD ILE L 48 C ILE L 48 O ILE L 48 N GLY L 49 CA GLY L 49 C GLY L 49 O GLY L 49 N GLY L 50 CA GLY L 50 C GLY L 50 O GLYL 50 N THRL 51 CA THRL 51 CB THRL 51 OG1 THR L 51 CG2 THR L 51 C THRL 51 O THRL 51 N ASN L 52 CA ASN L 52 CB ASN L 52 CG ASN L 52 ODI ASN L 52 ND2 ASN L 52 10.846 -1.269 10.255 -1.929 12.002 -0.541 10.796 -1.866 12.566 -0.471 11.954 -1.135 8.986 -0.319 4 8.261 -1.106 4 9.655 0.615 9.527 0.762 8.316 1.644 8.095 1.663 8.557 3.064 10.787 1.386 11.314 2.243 11.317 0.861 12.535 1.388 12.250 2.581 11.266 2.582 13.086 3.592 12.912 4.859 13.083 6.035 12.285 5.959 7.917 1.00 8.20 8.985 1.00 10.99 8.127 1.0013.17 10.252 1.00 11.48 9.394 1.00 12.05 10.462 1.00 12.67 .731 1.00 14.13 4.146 1.00 14.69 4.100 1.00 14.63 2.686 1.00 12.14 2.361 1.00 14.73 0.958 1.0025.05 2.814 1.00 19.97 2.187 1.00 11.69 2.824 1.00 9.53 1.096 1.00 11.34 0.532 1.00 7.20 0.326 1.00 7.78 -1.130 1.00 10.42 0.168 1.00 7.54 -0.884 1.00 7.47 0.087 1.00 6.90 1.375 1.00 6.26 12.862 6.905 2.403 1.00 11.14 10.820 6.197 1.085 1.00 2.41 13.940 4.988 -2.015 1.00 5.84 13.563 5.288 -3.139 1.00 8.92 15.209 4.749 -1.675 1.00 9.03 16.350 4.907 -2.568 1.00 7.03 17.257 6.079 -2.090 1.00 7.21 18.525 6.173 -2.924 1.00 9.51 16.497 7.409 -2.042 1.00 8.82 16.008 7.937 -3.363 1.00 7.80 17.230 3.640 -2.525 1.00 8.61 17.458 3.073 -1.451 1.00 10.60 17.740 3.224 -3.700 1.00 7.04 18.702 2.140 -3.794 1.00 2.00 19.833 2.557 -4.709 1.00 7.57 19.696 3.467 -5.544 1.00 14.41 20.957 1.959 -4.582 1.00 9.91 22.027 2.316 -5.453 1.00 9.21 22.297 3.805 -5.479 1.00 12.31 22.358 4.388 -6.535 1.00 12.48 22.456 4.402 -4.305 1.00 10.33 22.787 5.841 -4.140 1.00 12.06 24.098 6.283 -4.882 1.00 11.87 25.218 5.449 -4.521 1.00 7.57 24.449 7.719 -4.497 1.00 11.63 21.668 6.825 -4.481 21.346 7.664 -3.651 21.034 6.712 -5.662 20.063 7.719 -6.076 20.764 8.826 -6.841 21.598 8.273 -7.968 1.00 11.67 1.00 11.93 1.00 12.21 1.00 13.73 1.00 18.43 1.00 24.37 21.193 7.327 -8.623 1.00 22.65 22.788 8.821 -8.173 1.0028.21 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -219-

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476 477 478 480 481 482 483 484 487 488 489 491 492 493 494 495 497 498 501 504 505 506 508 509 510 511 512 513 514 515 516 517 518 519 521 522 523 524 526 527 528 529 530 531 532 533 534 535 536 537 538 539 541 542 543 544 C ASNL 52 0 ASNL 52 N ASNL 53 CA ASN L 53 GB ASN L 53 CG ASN L 53 ODI ASN L 53 ND2 ASN L 53 C ASNL 53 O ASN L53 N ARGL 54 CA ARG L 54 GB ARG L 54 CG ARG L 54 CD ARG L 54 NE ARG L 54 CZ ARG L 54 NH IARG L 54 NH2 ARG L 54 C ARGL 54 O ARG L 54 N ALAL 55 CA ALA L 55 GB ALA L 55 C ALAL 55 O ALA L55 N PRO L56 CD PRO L 56 CA PRO L 56 GB PRO L 56 CG PRO L 56 18.943 18.295 18 .726 17.637 18.056 17.181 17.66z 15.90: 16.409 16.369 15.431 14.269 13.494 12.114 11.818 12. 156 11.305 11.67 10.08 7.197 -6.931I 1.00 15.37 7.964 -7.613 1.00 13.37 5.906 -6.928 1.00 16.28 5.343 -7.691 1.00 17.34 3.969 -8.244 1.00 24.00 3.420 -9.373 1.00 27.36 2.624-10.199 1.0033.10 13.812 -9.439 1.00 31.42 5.216 -6.784 1.00 17.91 4.427 -5.870 1.00 18.29 6.003 -7.032 1.00 15.93 5.978 -6.237 1.00 18.87 7.239 -6.542 1.00 22.33 7.315 -5.958 1.0025.55 8.740 -5.619 1.00 29.54 9.611 -6.703 1.00 27.82 9.903 -7.653 1.00 32.19 6 10.7 13 -8.622 1.00 35.27 0 9.380 -7.644 1.00 31.58 C PRO L56 O PROL 56 N GLY L57 GA GLY L 57 C GLYL 57 O GLYL 57 N VALL 58 CA VAL L 58 GB VAL L 58 CG1IVAL L 58 CG2 VAL L 58 C VALL 58 O VAL L58 N PRO L59 CD PRO L 59 GA PRO L 59 CB PRO L 59 CG PRO L 59 C PROL 59 O PRO L59 N ALA L60 CA ALA L 60 CB ALA L 60 C ALAL 60 0 ALAL 60 13.462 4.730 -6.545 1.00 21.41 13.238 4.418 -7.734 1.0021.21 13.049 4.008 -5.480 1.00 20.79 12.226 2.802 -5.620 1.00 21.50 11.976 2.164 -4.253 1.00 18.92 10.925 3.180 -6.285 1.0022.01 10.492 4.311 -6.184 1.0023.44 10.249 2.257 -6.952 1.00 25.55 10.577 0.805 -7.061 1.00 26.77 9.009 2.580 -7.645 1.0024.82 8.686 1.274 -8.405 1.00 27.53 9.270 0.215 -7.526 1.0027.71 7.903 3.030 -6.696 1.00 25.91 7.736 2.500 -5.588 1.0026.27 7.138 4.016 -7.146 1.00 26.28 6.045 4.544 -6.338 1.00 22.74 6.471 5.629 -5.360 1.0020.96 5.654 6.415 -4.928 1.0023.79 7.749 5.670 -4.998 1.00 20.25 8.228 6.677 -4.084 1.00 18.53 9.676 6.383 -3.720 1.00 15.29 10.261 7.548 -2.974 1.00 11.07 9.742 5.104 -2.893 1.00 12.65 8.120 8.092 -4.688 1.00 22.04 8.591 8.337 -5.814 1.00 22.18 7.523 9.061 -3.910 1.00 21.50 6.971 8.873 -2.543 1.00 20.50 7.338 10.464 -4.326 1.00 17.94 6.866 11.147 *-3.063 1.00 18.92 6.066 10.068 -2.423 1.00 18.97 8.586 11.100 -4.852 1.00 16.82 9.708 10.921 -4.327 1.00 15.46 8.374 11.880 -5.867 1.00 13.05 9.448 12.535 -6.530 1.00 14.83 8.866 13.317 -7.685 1.00 14.69 10.238 13.427 -5.574 1.00 13.44 11.412 13.644 -5.782 1.00 12.14 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -220- ATOM 545 N ARG L 61 9.601 13.919 -4.488 1.00 15.30

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547 548 549 550 551 553 554 557 560 561 562 564 565 566 567 568 569 570 571 572 573 574 576 577 578 580 581 582 584 585 586 587 589 590 591 593 594 595 597 598 599 600 601 602 603 604 606 607 608 609 610 611 612 613 615

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ARG L ARG L ARG L ARG L ARG L ARG L NHI ARG L 61 NH2 ARG L 61 C ARGL 61 O ARG L 61 N PHE L 62 CA PHE L 62 CB PHE L 62 CG PHE L 62 CDI PHE L 62 CD2 PHE L 62 CEI PHE L 62 CE2 PHE L 62 CZ PHE L 62 C PHE L 62 O PHE L 62 N SER L 63 CA SER L 63 CB SERL 63 OG SER L 63 C SERL 63 O SERL 63 N GLY L 64 CA GLY L 64 C GLY L 64 O GLY L 64 N SER L 65 CA SER L 65 CB SER L 65 OG SER L 65 C SER L 65 O SERL 65 N LEU L 66 CA LEU L 66 CB LEU L 66 CG LEU L 66 SCDI LEU L 66 CD2 LEU L 66 C LEU L 66 O LEU L 66 N ILE L 67 CA ILE L 67 CB ILE L 67 CG2 ILE L 67 SCGI ILE L 67 CD ILE L 67 C ILEL 67 O ILEL 67 N GLY L 68 CA GLY L 68 10.313 9.351 8.625 7.915 7.241 6.124 5.532 5.617 11.499 12.289 11.648 1 12.755 12.288 11.285 11.712 9.924 10.780 8.998 9.424 1 13.913 1 13.679 1 15.160 1 16.310 16.686 17.272 17.512 1 17.714 1 18.284 19.500 20.685 20.628 21.761 22.876 22.603 22.777 24.064 1 23.959 25.194 14.385 15.063 14.100 13.482 12.60C 13.726 14.160 14.863 2.826 12.125 10.734 10.782 -1.596 -0.415 0.466 0.102 0.889 S-1.066 -2.810 -2.103 -2.955 -2.302 -1.773 -0.645 1.00 14.79 1.00 14.00 1.00 10.99 1.00 11.79 1.00 10.75 1.00 9.70 14.815 -3.524 1.00 12.59 15.398 -2.478 1.00 11.72 1.00 12.82 1.00 14.41 1.00 11.27 1.00 10.94 1.00 9.35 1.00 9.62 1.00 5.49 1.00 6.68 1.00 2.51 1.00 7.73 10.900 0.694 10.700 -0.909 10.933 1.709 10.735 0.116 10.854 1.936 11.434 2.336 12.117 13.360 14.327 1.684 12.184 1.425 -3.265 -4.344 -2.872 -3.737 -4.530 -3.676 -2.949 -1.861 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 4.66 9.16 8.82 4.85 8.59 7.17 12.90 7.30 9.45 10.714 -3.503 10.258 -2.891 10.879 -3.565 11.253 -4.757 11.034 -2.869 11.673 -3.482 13.184 -3.669 13.907 -2.443 11.432 -2.648 10.685 -1.670 11.991 -3.078 1.00 5.56 1.00 4.07 1.00 9.49 1.00 12.20 1.00 6.73 1.00 9.75 1.00 8.17 1.00 10.45 1.00 10.16 1.00 10.96 1.00 10.68 26.460 11.858 -2.382 1.00 9.69 27.453 11.096 -3.303 1.00 13.61 28.203 9.827 -2.816 1.00 9.87 27.339 8.952 -1.958 1.00 8.09 28.667 9.029 -4.026 1.00 8.69 26.931 13.303 -2.134 1.00 12.92 27.044 14.080 -3.070 1.00 10.87 27.136 13.678 -0.858 1.00 12.45 27.577 15.035 -0.515 1.00 11.66 26.479 15.768 0.341 1.00 12.96 26.874 17.196 0.608 1.00 13.30 25.123 15.753 -0.357 1.00 13.53 24.013 16.437 0.425 1.00 11.05 28.879 14.904 0.276 1.00 12.31 28.896 14.327 1.350 1.00 13.03 29.987 15.387 -0.260 1.00 13.08 31.238 15.196 0.431 1.00 12.32 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCTIG B98/02 542 -22 1-

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616 617 618 620 621 622 623 624 625 626 627 629 630 631 632 633 634 638 639 640 642 643 644 645 646 648 649 650 651 652 654 655 656 657 658 659 660 661 663 664 665 667 668 669 670 672 673 674 675 676 677 678 679 681 682 683 C GLY L68 0 GLY L68 N ASP L69 CA ASP L 69 GB ASP L 69 CG ASP L 69 OD I ASP L 69 0D2 ASP L 69 C ASP L69 0 ASP L69 N LYSL 70 CA LYS L 70 GB3 LYS L 70 CG LYS L 70 CD LYS L 70 CE LYS L 70 NZ LYS L 70 C LYS L70 0 LYS L70 N ALA L71 CA ALA L 71 CB ALA L 71 C ALAL 71 O ALA L71 N ALA L72 CA ALA L 72 GB ALA L 72 C ALA L72 0 ALA L72 N LEU L73 CA LEU L 73 GB3 LEU L 73 CG LEU L 73 CD I LEU L 73 CD2 LEU L 73 C LEU L73 0 LEU L73 N THR L74 CA THR L 74 GB THR L 74 OG I THR L 74 CG2 THR L 74 C THR L74 O THR L 74 N ILE L75 CA ILE L 75 GB ILE L 75 GG2 ILE L 75 GI ILE L 75 GD ILE L 75 C ILEL 75 O ILE L 75 N THR L76 CA THR L 76 GB THR L 76 OGI THRL 76 3 1.485 3 1.193 3 1.987 32.247 33.366 34.6 18 13 .701I 12.93 9 13.249 11.813 11.533 12.344 0.579 1.00 17.92 .0.379 1.00 16.67 1.750 1.00 16.48 1.933 1.00 18.10 2.931 1 .00 24.05 2.727 1.00 31.27 1.596 1.00 32.40 3.724 1.00 39.08 35.210 12.318 35.021 13.019 31.040 11.037 2.437 1.00 14.56 3 1.214 9.924 2.915 1.00 16.00 29.837 11.568 28.688 28.116 28.992 28.255 28.208 29.587 27.589 1 27.473 1 26.762 25.546 25.071 24.490 24.528 23.549 22.564 23.027 21.207 21.089 20.183 18.796 17.970 16.498 10.854 11.608 11.536 12.102 13 .604 14. 158 0.639 1.369 9.623 9.487 8.044 10.404 10.675 10.888 11.807 13.252 11.564 11.053 11.857 11.776 10.826 10.785 2.3 19 2.852 4.037 5.269 6.467 6.394 6.382 1.872 0.883 2.137 1.377 1.378 2.020 3.25 1 1.230 1.734 1.51: 1.102 -0.049 1.885 1.44 2.30', 1.93 0.654 1.00 11.13 1.0011.46 1.00 11.39 1.00 18.50 1.0020.15 1.00 22.74 1.00 27.69 1.00 10.75 1.00 11.35 1.00 6.32 1.00 2.44 1.00 2.00 1.00 6.77 1.00 6.10 1.00 5.00 6 1.00 6.21 S1.00 3.82 1.00 4.44 1.00 6.60 1.00 5.08 5 1.00 4.01 1.00 4.42 6 1.00 4.74 6 1.00 4.42 16.312 9.970 15.675 10.211 3.083 1.00 8.67 18.191 13.148 1.579 1.00 5.38 18.287 13.764 2.621 1.00 9.62 17.593 13.629 0.537 1.00 7.72 16.998 14.928 0.562 1.00 6.80 17.695 15.896 -0.460 1.00 9.87 19.076 16.149 -0.017 1.00 4.69 16.936 17.208 -0.559 1.00 4.65 15.571 14.855 0,277 1.00 7.31 15.153 14.227 -0.676 1.00 6.60 14.799 15.464 1.142 1.00 8.15 13.396 15.553 0.932 1.00 9.10 12.611 15.126 2.187 1.00 11.95 11.132 15.053 1.856 1.00 12.49 13.152 13.789 2.734 1.00 16.99 12.418 13.281 3.963 1.00 15.52 13.081 17.010 0.632 1.00 12.05 13.212 17.857 1.514 1.00 10.42 12.693 17.302 -0.620 1.00 13.27 12.379 18.674 -1.036 1.00 11.86 12.740 18.887 -2.519 1.00 8.49 14.102 18.539 -2.723 1.00 7.34 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -222-

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685 CG2 THR L 76 686 C THR L 76 687 0 TH-R L 76 688 N GLY L77 690 CA GLY L 77 691 C GLY L 77 692 0 GLY L77 693 N ALA L 78 695 CA ALA L 78 696 CB ALA L 78 697 C ALA L 78 698 0 ALA L78 699 N GLN L79 701 CA GLN L 79 702 CB GLN L 79 703 CG GLN L 79 704 CD GLN L 79 705 OEI GLN L 79 706 NE2 GLN L 79 709 C GLN L 79 710 0 GLN L79 711 N THR L 80 713 CA THR L 80 714 CB THR L 80 715 OG ITHR L 80 717 CG2 THR L 80 718 C THR L 80 719 0 THR L 80 720 N GLUL 81 722 CA GLU L 81 723 CB GLU L 81 724 CG GLU L 81 725 CD GLU L 81 726 OEI GLU L 81 727 OE2 GLU L 81 728 C GLUL 81 729 0 GLU L 81 730 N ASP L 82 732 CA ASP L 82 733 CB ASP L 82 734 CG ASP L 82 735 ODI ASP L 82 736 0D2 ASP L 82 737 C ASP L 82 738 0 ASP L 82 739 N GLU L83 741 CA GLU L 83 742 CB GLU L 83 743 CG GLU L 83 744 CD GLU L 83 745 OEI GLU L 83 746 0E2 GLU L 83 747 C GLU L83 748 0 GLU L 83 749 N ALA L84 751 CA ALA L 84 12.546 20.321 -2.892 1.00 8.93 10.893 18.986 10.044 18.392 10.567 19.944 9.167 20.257 8.560 19.175 7.497 18.653 9.237 18.824 8.765 17.723 9.674 17.601 7.298 17.890 6.811 18.996 6.571 16.773 5.184 16.787 4.397 16.061 4.447 16.805 3.680 16.127 3.849 16.479 2.817 15.163 4.972 16.160 5.861 15.498 3.796 16.364 3.552 15.895 2.186 16.359 1.189 15.931 2.139 17.881 3.606 14.380 4.000 13.812 .0.861 1.00 15.75 .1.538 1.00 19.95 0.019 1.00 17.30 0.271 1.00 15.95 1.109 1.00 16.40 0.784 1.00 17.47 2.193 1.00 16.13 3.068 1.00 16.88 4.282 1.00 15.72 3.483 1.00 17.09 3.691 1.0020.02 3.535 1.00 16.23 3.933 1.00 14.31 2.875 1.00 13.55 1.555 1.00 17.28 0.447 1.00 22.72 -0.737 1.00 28.20 0.790 1.00 22.58 5.327 1.00 14.89 5.849 1.00 14.38 5.919 1.00 12.50 7.291 1.00 18.91 7.810 1.00 17.20 6.884 1.00 21.04 7.940 1.00 19.65 7.362 1.00 19.00 8.394 1.00 21.72 6.252 1.00 18.63 6.104 1.00 19.81 4.801 1.00 24.17 3.585 1.00 34.44 2.25 1 F.0040.56 1.960 1.00 44.10 1.479 1.00 43.81 6.097 1.00 18.55 6.062 1.00 20.36 6.113 1.00 14.45 6.091 1.00 11.96 5.268 1.00 11.90 3.783 1.00 13.46 3.2 15 3.235 2.555 3.338 2.657 1.603 3.18( 4.660 4.853 5.665 7.027 7.902 7.523 13.759 12.325 11.956 12.428 12. 143 112.792 11.280 11.785 10.588 12.663 12.212 13.160 13.2 14 6.822 12.310 3.288 1.00 16.83 7.906 14.176 3.131 1.00 13.86 7.608 12.087 7.492 1.00 12.84 8.798 11.739 7.639 1.00 9.40 6.844 12.479 8.535 1.00 13.25 7.360 6.371 6.849 6.097 5.8 12 5.781 12.253 12.783 12.635 13 .555 14.703 13.123 9.890 1.00 13.46 10.953 1.00 17.14 12.411 13.38S 13.01 14.53 9.996 9.8 19 10.224 10.2 18 *1.00 21.93 1.00 26.14 8 1.00 22.27 1 1.00 27.48 1.00 9.35 1.00 12.41 1.00 9.86 1.00 8.78 7.522 10.729 6.538 10.002 8.733 10.261 9.002 8.826 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 990379CT/GB98/02542 -223-

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752 753 754 755 757 758 759 760 761 762 763 764 766 767 768 .769 770 771 772 773 774 776 777 778 780 781 782 783 784 785 786 787 788 789 790 792 793 794 795 796 797 799 800 801 802 803 805 806 807 808 809 810 811 812 814 815 CB ALA L 84 C ALA L84 0 ALA L84 N ILE L85 CA ILE L 85 GB ILE L 85 CG2 ILE L 85 CG I ILE L 85 CD ILE L 85 C ILE L851 0 ILE L85 N TYR L86 CA TYR L 86 CB TYR L 86 CG TYR L 86 CIDI TYR L 86 GEl TYR L 86 CD2 TYR L 86 CE2 TYR L 86 CZ TYR L 86 OH TYR L 86 C TYR L 86 O TYR L 86 N PHE L87 CA PHE L 87 GB PHE L 87 CG PHE L 87 CDI PHE L 87 CD2PHEL 87 GEl PHEL 87 CE2 PHE L 87 CZ PHE L 87 C PHE L87 0 PHE L87 N CYSL 88 GA CYS L 88 GB CYS L 88 SG GYS L 88 C CYS L88 O CYSL 88 N ALA L89 CA ALA L 89 GB ALA L 89 C ALA L89 0 ALA L89 N LEUL 90 GA LEU L 90 GB LEU L 90 GG LEU L 90 CDI LEU L 90 GD2 LEU L 90 C LEUL 90 O LEUL 90 *N TRPL 91 GA TRP L 91 C B TRP L 91 8.680 10.451 11. 142 0.935 12.374 12.587 14.073 11.812 11.467 8.265 8.839 1.00 7.20 8.635 10.544 1.00 8.36 9.614 10.771 1.00 11.79 7.404 10.597 1.00 8.82 7.195 10.869 1.00 7.36 6.155 11.972 1.00 5.25 5.990 12.304 1.00 9.66 6.631 13.206 1.00 13.36 5.568 14.201 1.00 10.12 12.996 6.745 9.551 1.00 5.85 12.329 6.082 8.770 1.00 6.76 14.192 7.215 9.275 1.00 4.42 14.866 15.159 13.913 13.172 11.924 13 .369 12.111 11.391 10.104 16.153 16.996 16.301 17.557 17.251 16.602 17.366 15.220 16.743 14.595 15 .365 18.328 17.707 19.641I 20.434 2 1.404 22.767 21.204 2 1.483 2 1.489 22.254 2 1.298 23.388 23. 165 24.596 25.735 26.855 26.569 6.918 7.986 1.00 7.23 8.203 7.200 1.00 6.83 8.870 6.716 1.00 8.61 9.704 7.586 1.00 5.73 10.187 7.218 1.00 8.65 8.555 5.449 1.00 5.92 9.039 5.092 1.00 6.08 9.850 5.989 1.00 8.14 10.252 5.681 1.00 6.40 6.242 8.233 1.00 2.00 6.769 8.949 1.00 8.00 5.063 7.681 1.00 5.92 4.307 2.842 2.687 2.481 2.729 2.308 2.5 62 2.348 4.303 4.281 4.3 10 4.144 5.297 5.371 2.852 2.4 13 2.2 13 0.975 -0.20: 1.099 1.628 0.655 0.735 1.595 3.094 7.841 1.00 4.34 8.184 1.00 8.38 9.499 1.00 9.99 10.618 1.00 6.06 I9.601 1.00 13.30 11.862 1.00 10.61 10.826 1.00 14.04 11.957 1.00 8.48 6.562 1.00 3.22 5.510 1.00 2.51 6.649 1.00 5.93 5.459 1.00 9.35 5.251 1.00 5.49 6.415 1.00 15.50 5.597 1.00 8.53 6.720 1.00 8.84 4.498 1.00 8.42 4.533 1.00 8.94 4.212 1.00 6.42 3.503 1.00 11.22 2.418 1.00 10.12 3.854 1.00 12.71 2.957 1.00 12.28 3.564 1.00 13.85 I3.774 1.00 10.32 27.882 3.794 25.941 3.694 26.287 -0.669 26.362 -1.520 26.696 -0.882 27.201 -2.184 26.734 -2.435 4.141 2.50: 2.660 3.582 1.373 0.894 -0.548 11.00 7.96 1.00 10.49 1.00 14.32 1.00 14.08 1.00 10.21 1.00 9.56 1.00 13.24 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -224-

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816 CG TRPL 91 817 CD2TRPL 91 818 CE2TRPL 91 819 CE3 TRP L 91 820 CDI TRPL 91 821 NEI TRPL 91 823 CZ2 TRP L 91 824 CZ3 TRP L 91 825 CH2 TRP L 91 826 C TRPL 91 827 O TRPL 91 828 N TYR L 92 830 CA TYR L 92 831 CB TYRL 92 832 CG TYR L 92 833 CDI TYR L 92 834 CEI TYRL 92 835 CD2 TYRL 92 836 CE2 TYR L 92 837 CZ TYRL 92 838 OH TYRL 92 840 C TYRL 92 841 O TYRL 92 842 N SERL 93 844 CA SERL 93 845 CB SERL 93 846 OG SERL 93 848 C SERL 93 849 O SERL 93 850 N ASN L 94 852 CA ASN L 94 853 CB ASNL 94 854 CG ASN L 94 855 ODI ASN L 94 856 ND2 ASN L 94 859 C ASN L 94 860 O ASN L 94 861 N HISL 95 863 CA HIS L 95 864 CB HIS L 95 865 CG HIS L 95 866 CD2 HIS L 95 867 NDI HIS L 95 869 CEl HIS L 95 870 NE2 HIS L 95 872 C HISL 95 873 O HIS L 95 874 N TRPL 96 876 CA TRPL 96 877 CB TRPL 96 878 CG TRPL 96 879 CD2 TRP L 96 880 CE2 TRP L 96 881 CE3 TRP L 96 882 CDI TRP L 96 883 NEI TRP L 96 27.370 -3.606 -1.295 1.00 16.93 26.974 -5.018 -1.253 1.00 18.28 27.660 26.094 28.273 28.432 27.509 25.935 -5.679 -5.782 -3.498 -4.721 -7.069 -7.162 3 26.650 -7.793 28.684 -2.211 0 29.339 -1.272 C 29.220 -3.247 30.649 -3.389 31.124 -3.365 30.902 -2.043 29.753 -1.810 29.535 -0.583 31.836 -1.015 31.622 0.197 30.472 0.415 30.237 1.671 31.066 -4.693 31.333 -5.699 31.044 -4.664 31.475 -5.795 32.907 -6.178 -2.29 -0.455 -2.32( -2.90: -2.564 -0.72 -1.78: .955 >.509 1.556 1.63( 3.095 3.827 4.59 5.21 3.73 4.345 5.077 5.601 ).951 1.630 ).393 -1.251 -0.911 1 1.00 18.63 5 1.00 18.52 0 1.00 18.74 2 1.00 18.84 1 1.00 17.39 6 1.00 20.45 2 1.00 18.96 1.00 8.96 1.00 9.38 1.00 9.41 S1.00 10.88 1.00 13.13 7 1.00 12.25 1 1.00 15.61 9 1.00 11.01 0 1.00 14.35 5 1.00 12.95 1.00 11.34 1.00 14.51 1.00 15.14 1.00 14.53 1.00 16.81 1.00 18.41 1.00 19.53 33.774 -5.132 -1.332 1.00 25.55 30.582 -7.038 -1.232 1.00 20.20 30.266 -7.607 -2.311 1.00 17.43 30.200 -7.482 -0.020 1.00 19.09 29.417 -8.684 0.119 1.00 19.31 30.343 -9.906 0.036 1.00 18.06 31.362 -9.915 1.145 1.00 22.80 31.381 -9.018 2.021 1.0022.03 32.219-10.924 1.140 1.00 21.52 28.618 -8.688 1.425 1.0020.27 28.207 -9.740 1.908 1.00 22.39 28.396 -7.508 2.003 1.00 19.53 27.542 -7.405 28.273 29.434 30.655 29.472 30.652 31.371 -7.846 -6.995 -6.852 -6.234 -5.659 -6.031 3.172 1.00 18.65 4.411 1.00 16.28 4.785 1.00 19.96 4.227 1.00 17.79 5.944 1.00 20.98 6.104 1.00 22.66 5.064 1.00 20.00 3.352 1.00 17.00 2.790 1.00 16.62 4.147 1.00 15.07 2 2 .7.026 -5.989 27.564 -5.066 25.985 -5.837 25.383 -4.537 23.884 -4.547 23.550 -4.745 23.350 -3.71 22.934 -4.34( 23.475 -2.31 23.265 -5.91 22.893 -5.67 1 0 1 9 7 4.360 1.00 13.84 4.040 1.00 12.09 2.591 1.00 14.83 1.602 1.00 12.10 0.417 1.00 13.36 1.612 1.00 11.19 1.979 1.00 15.53 0.692 1.00 14.17 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -225-

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885 CZ2 TRP L 96 886 CD3 TRP L 96 887 CH2 TRP L 96 888 C TRP L 96 889 0 TRP L96 890 N VAL L97 892 CA VAL L 97 893 CB VAL L 97 894 CG I VAL L 97 895 CG2 VAL L 97 896 C VAL L97 897 0 VAL L97 898 N P-E L 98 900 CA PHE L 98 901 GB PHE L 98 902 CG PHE L 98 903 CD1I PHE L 98 904 CD2 PHE L 98 905 GEl PHE L 98 906 CE2 PHE L 98 907 CZ PHE L 98 908 C PHE L 98 909 0 PHE L98 910 N GLY L99 912 CA GLY L 99 913 C GLY L 99 914 0 GLY L99 915 N GLYLI100 917 CA GLY L 100 918 C GLYLIQO 919 0 GLYL 100 920 N GLYLI101 922 CA GLY L 101 923 C GLYL 101 924 0 GLYLI101 925 N THRLI102 927 CA THR L 102 928 GB THR L 102 929 OGI THR L 10' 931 GG2 THR L 102 932 C THR L 102 933 0 THR L 102 934 N LYS L 103 22.643 -3.626 23.181 -1.602 22.774 -2.257 25.501 -4.165 5 25.45 1 -5.057 25.664 -2.859 25.612 -2.292 26.971 -1.817 26.881 -1.178 27.865 -3.039 -0.760 1.00 9.46 0.451 1.00 7.52 -0.716 1.0011.56 .786 1.00 14.61 .646 1.00 12.87 6.014 1.00 11.97 7.355 1.00 13.35 7.809 1.00 12.63 9.180 1.00 14.09 7.849 1 .00 8.66 24.600 -1.158 24.581 -0.311 23.666 -1.233 22.629 -0.239 21.317 -0.875 20.505 -1.489 20.799 -2.748 19.392 -0.848 7.382 6.477 8.342 8.458 8.885 7.798 7.325 7.326 6.4 10 6.398 5.932 1.00 14.93 1.00 9.72 1.00 13.01 1.00 12.29 1.00 9.91 1.00 7.44 1.00 9.14 1.00 6.37 1.00 6.90 1.00 8.01 1.00 7.78 19.985 18.557 18.849 23.034 23.871 22.517 22.775 2 1.797 20.892 21.971 -3.342 -1.432 -2.688 0.838 0.596 2.053 3.153 3.085 2.267 3.955 9.452 1.00 11.91 10.313 1.00 11.43 9.239 1.00 14.08 10.134 1.00 12.11 11.289 1.00 11.79 11.267 1.00 10.46 12.280 1.00 12.00 21.103 3.943 13.451 1.00 8.79 19.723 4.507 13.256 1.00 9.23 18.832 4.282 14.101 1.00 12.86 19.494 5.204 12.159 1.00 7.60 18.172 5.776 11.925 1.00 4.00 18.149 7.204 12.428 1.00 7.52 18.914 7.549 13.399 1.00 7.76 17.410 8.046 11.676 1.00 8.12 17.197 9.482 11.996 1.00 7.96 17.621 10.421 10.792 1.00 7.52 19.018 10.307 10.564 1.00 4.45 17.291 11.883 11.056 1.00 4.44 LYS L 103 LYS L 103 iLYS L 103 LYS L 103 LYS L 103 LYS L 103 LYS L 103 LYS L 103 LEU L 104 LLEU L 104 1LEU L 104 15 .717 14.961 15.248 13 .807 13.261 11.801 11.212 9.750 8.858 13.468 14.030 12.546 10.189 10.407 10.443 10.989 11.110 11.551 10.636 11.724 12.728 11.725 13 .349 13.447 14.902 14.933 16.350 16.305 15.481 12.798 13.180 11.853 1.00 10.41 1.00 11.36 1.00 14.52 1.00 16.54 1.00 12.70 1.00 14.64 1.00 17.17 1.00 10.60 1.00 12.19 1.00 9.69 9.657'12.207 1.00 10.01 9.267 11.332 1.00 11.13 12.183 12.968 12.125 12.864 11.724 14.187 12.847 15.212 11.229 1.00 11.35 9.693 1.00 9.61 9.012 1.00 10.81 9.199 1.00 2.00 ATOM 951 CG LEU L 104 ATOM 952 CD1I LEU L 104 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PTG9/24 PCT/GB98/02542 -226-

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953 954 955 956 958 959 960 962 963 964 965 967 968 969 970 971 972 973 975 976 977 978 979 980 981 982 984 985 986 987 989 990 991 993 994 995 997 998 999 1000 1001 1002 1003 1004 1005 1007 1008 1009 1010 1011 1012 1016 1017 1018 1 020 CD2 LEU L 104 C LEU L 104 O LEU L 104 N THR L 105 CA THR L 105 GB THR L 105 OGI THR L 105 CG2 THR L 105 C THR L 105 O THR L 105 N VAL L 106 CA VAL L 106 GB VAL L 106 CG I VAL L 106 CG2 VAL L 106 C VAL L 106 O VAL L 106 N LEUL 106A CA LEU L 106A GB LEULI106A CG LEULI106A CD I LEU L 106A CD2 LEU L 1 06A C LEULI106A O LEULI106A N GLY L 107 CA GLY L 107 C GLY L 107 O GLY L 107 N SER L 108 CA SER L 108 GB SER L 108 OG SER L 108 C SER L 108 O SER L 108 N GLU L 109 CA GLU L 109 GB GLU L 109 CG GLU L 109 CD GLU L 109 OEI GLU L 109 OE2 GLU L 109 C GLU L 109 0 GLU L 109 N LYSL 110 11.408 13.947 7.560 1.00 10.86 10.866 13.484 11.728 1.00 10.04 9.862 12.794 11.656 1.00 16.01 10.861 14.711 12.251 1.00 11.71 9.614 15.361 12.576 1.00 7.07 9.682 16.091 13.949 1.00 9.46 9.844 15.129 14.983 1.00 12.27 8.415 16.918 14.200 1.00 2.15 9.271 16.410 11.513 1.00 7.56 10.093 17.241 11.182 1.00 9.71 8.084 16.320 10.974 1.00 9.73 7.541 17.364 10.106 1.00 11.58 7.106 16.851 8.725 1.00 9.06 6.526 18.000 7.911 1.00 6.52 8.329 16.228 8.011 1.00 10.40 6.335 17.931 10.856 1.00 11.09 5.242 17.324 10.877 1.00 13.54 6.601 19.071 11.521 1.00 12.43 5.655 19.710 12.378 1.00 12.13 6.116 21.132 12.666 1.00 9.12 7.488 21.225 13.349 1.00 7.72 7.990 22.640 13.270 LOO 9.05 7.413 20.730 14.816 1.00 6.98 4.325 19.678 11.752 1.00 13.07 4.094 20.360 10.779 1.00 18.75 3.468 18.816 12.284 1.00 14.91 2.117 18.689 11.760 1.00 16.40 1.065 -0.112 1.523 0.647 0.095 1.115 19.137 18.925 19.742 20.251 19. 123 18.543 1.453 21.165 2.676 21.208 0.776 21.825 1.409 22.77.

0.305 23.56: -0.525 24.46 1.319 23.7 -1.764 22.6 -1.502 24.3 12.762 12.547 13 .859 14.907 15.790 116.596 15 .760 15.641 16.671 5 17.516 2 18.224 8 17.32( 12 16.23 14 16.5( 09 15.1( 18.513 I18.956 18.883 4 19.84: 4 19.99: 7 18.75w 6 18.83: 3 17.5 1 6 17.61 21.187 21.557 21.876 5 23.151 4 22.92) 1.00 15.29 1.00 16.64 1.00 18.60 1.00 18.91 1.00 21.02 1.00 27.15 1.00 17.58 1.00 17.99 1.00 17.83 1.00 16.58 1.00 21.42 )1.00 26.54 4 0.50 27.76 )2 0.50 28.73 )4 0.50 26.82 1.00 17.20 1.00 14.41 1.00 16.72 5 1.00 20.99 1.00 22.20 9 1.00 24.75 5 1.00 25.15 11.00 30.78 1 1.00 32.12 1.00 21.68 1.00 22.35 1.00 22.71 8 1.00 21.05 1 1.00 22.18 LYS L 110 LYS L 110 LYS L 110 LYS L 110 LYS L 110 LYS L 110 LYS L 110 LYS L 110 SER L 111 SER L III 2.287 1.9 15 3.430 4.266 5.6 18 6.477 7.786 8.531 9.941 3.566 2.769 3.834 3.196 2.113 22.041 20.961 22.599 21.91 22.58.

22.37 23.12 23.02: 23.51 Z 1.804 22.673 20.699 20.39 19.35.

ATOM 1021 GB SER L II I SUBSTITiUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -227-

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1022 OG SER L IlIt 1024 C SERLIII 1025 0 SERL III 1026 N SERL 112 1028 CA SER L 112 1029 CB SER L 112 1030 OG SER L 112 1032 C SERL 112 1033 0 SER L 112 1034 N PROL 11 1035 CD PRO L 113 1036 CA PRO L 113 1037 CB PRO L 113 1038 CG PRO L 113 1039 C PRO L 113 1040 0 PRO L 113 1041 N SERL 114 1043 CA SER L 114 1044 CB SER L 114 1045 OG SER L 114 1047 C SERL 114 1048 0 SERL 114 1049 N VALLIIS 1051 CA VAL L 115 1052 CB VAL L 115 1053 CGI VAL L 115 1054 CG2 VAL L 115 1055 C VALL 115 1056 0 VAL L 115 1057 N THRL 116 1059 CA THR L 116 1060 CB THR L 116 1061 OGI THR L 116 1063 CG2 THR L 116 1064 C THR L 116 1065 0 THRL 116 1066 N LEUL 117 1068 CA LEU L 117 1069 CB LEU L 117 1070 CG LEU L 117 1071 CD1 LEU L 117 1072 CD2 LEU L 117 1073 C LEU L 117 1074 0 LEU L17 1075 N PHEL 118 1077 CA PHE L 118 1078 CB PHE L 118 1079 CG PHE L 118 1080 CDI PHE L 118 1081 CD2 PHE L 118 1082 CEI PHE L 118 1083 CE2 PHE L 118 1084 CZ PHE L 118 1085 C PHEL 118 1086 0 PHEL 118 1087 N PRO L 119 1.309 19.148 24.070 1.00 23.73 4.253 19.859 24.139 1.00 21.55 5.049 18.979 23.790 1.00 21.72 4.318 20.457 25.339 1.00 19.80 5.272 20.047 26.347 1.00 17.43 5.370 2 1.141 27.399 1.00 20.85 6.322 22.114 27.001 1.00 29.98 4.864 18.727 26.995 1.00 14.25 3.669 18.409 27.067 1.00 19.12 5.812 17.929 27.481 1.00 10.92 7.264 18.153 27.529 1.00 7.81 5.463 16.677 28.106 1.00 12.79 6.784 15.979 28.215 1.00 8.93 7.704 17.092 28.478 1.00 9.20 4.802 16.881 29.473 1.00 13.59 5.173 17.782 30.241 1.00 13.35 3.781 16.101- 29.736 1.00 15.55 3.219 16.052 3 1.062 1.00 15.08 1.722 15.844 31.000 1.00 17.33 1.154 15.908 32.312 1.0025.09 3.903 14.913 31.831 1.00 16.29 3.804 13.718 3 1.467 1.00 15.53 4.617 15.295 32.871 1.00 12.98 5.426 14.370 33.674 1.00 12.33 6.752 15.009 33.988 1.00 6.39 7.709 13.979 34.583 1.00 3.44 7.306 15.645 32.716 1.00 9.96 4.779 13.996 35.004 1.00 13.58 4.226 14.837 35.693 1.00 13.43 4.880 12.748 35.361 1.00 12.99 4.398 12.295 36.649 1.00 11.92 3.062 11.557 36.565 1.00 10.15 2.138 12.351 35.833 1.00 5.53 2.519 11.284 37.978 1.00 10.07 5.419 11.336 37.207 1.00 13.44 5.864 10.407 36.480 1.00 13.00 5.820 11.574 38.463 1.00 9.86 6.777 10.703 39.114 1.00 10.48 7.978 11.514 39.513 1.00 8.99 9.092 10.738 40.197 1.00 13.84 9.766 9.779 39.216 1.00 10.30 10.091 11.720 40.799 1.00 17.17 6.142 9.970 40.330 1.00 9.98 5.456 10.564 41.158 1.00 12.16 6.332 8.676 40.390 1.00 9.99 5.750 7.864 41.440 1.00 9.51 4.876 6.751 40.867 1.00 6.53 3.652 7.208 40.172 1.00 6.03 2.538 7.603 40.901 1.00 4.85 3.569 7.161 38.762 1.00 3.25 1.345 7.933 40.264 1.00 6.00 2.385 7.501 38.128 1.00 2.00 1.263 7.883 38.881 1.00 3.81 6.835 7.216 42.272 1.00 9.33 7.864 6.711 41.759 1.00 9.88 6.623 7.228 43.586 1.00 9.00 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/G B98/ 02542 -228-

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1088 CD PRO L 119 1089 CA PRO L 119 1090 GB PRO L 119 1091 CG PRO L 119 1092 C PRO L119 1093 0 PRO L 119 1094 N PRO L 120 1095 CD PRO L 120 1096 CA PRO L 120 1097 GB PRO L 120 1098 CG PRO L 120 1099 C PRO L 120 1100 0 PRO L 120 1101 N SER L 121 1103-GCA SER L 12 1 1104 GB SER L 121 1105 OG SER L 121 1107 C SER L 121 1108 0 SER L 121 1109 N SER L 122 1111 CA SER L 122 1112 GB SER L 122 1113 OG SER L 122 1115 C SER L 122 1116 0 SER L 122 1117 N ALALI123 1119 CA ALA L 123 1120 GB ALA L 123 1121 C ALA L 123 1122 0 ALA L 123 1123 N GLU L 124 1125 GA GLU L 124 1126 GB GLU L 124 1127 GG GLU L 124 1128 GD GLU L 124 1129 OE IGLU L 124 1130 OE2 GLU L 124 1131 C GLU L 124 1132 0 GLU L 124 1133 N LEU L 125 1135 GA LEU L 125 1136GCB LEU L 125 1137 GG LEU L 125 1138 CDI LEU L 125 1139 CD2 LEU L 125 1140 C LEU L125 1141 0 LEU L 125 1142 N GLULI126 1144 GA GLU L 126 1145 GB GLU L 126 1146 CG GLU L 126 1147 CD GLU L 126 1148 OE IGLU L 126 1149 OE2 GLU L 126 1150 C GLU L126 1151 0 GLU L 126 5.434 7.553 7.113 5.627 7.347 6.358 8.278 9.622 8.131 9.489 7.839 6.629 7.293 7.381 5.128 4.656 4.373 4.803 2.923 2.431 44.252 44 .549 45.852 45.676 44.604 44. 103 45. 160 45.475 45.298 45.730 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 7.59 8.55 9.62 9.04 4.72 6.50 3.79 6.28 6.76 9.39 10.182 3.627 46.233 1.00 5.45 7.022 2.552 46.275 1.00 10.87 6.768 3.266 47.252 1.00 11.35 6.290 1.505 45.965 1.00 12.02 5.183- 1.088 46.829 1.00 14.15 4.178 0.155 46.082 1.00 13.52 4.763 -1.084 45.722 1.00 14.31 5.748 0.403 48.072 1.00 15.89 6.927 -0.008 48.091 1.00 14.68 4.932 0.332 49.125 1.00 15.71 5.367 -0.320 50.342 1.00 17.27 4.344 -0.069 51.454 1.00 17.69 3.021 -0.3 19 50.990 1.00 25.59 5.508 -1.809 50.072 1.00 14.07 6.469 -2.436 50.541 1.00 16.14 4.563 -2.344 49.269 1.00 11.63 4.568 -3.775 48.940 1.00 10.10 3.326 -4.126 48.147 1.00 13.01 5.839 -4.151 48.206 1.00 9.75 6.494 -5.134 48.561 1.00 6.87 6.260 -3.325 47.226 1.00 8.37 7.492 -3.604 46.547 1.00 7.57 7.788 -2.653 45.376 1.00 9.85 9.105 -3.016 44.693 1.00 9.19 9.483 -2.129 43.532 1.00 8.89 8.883 -1.080 43.391 1.00 11.65 10.390 -2.478 42.764 1.00 10.96 8.648 -3.537 47.490 1.00 8.44 9.501 -4.428 47.481 1.00 7.83 8.687 -2.489 48.336 1.00 10.06 9.820 -2.290 49.278 1.00 8.99 9.562 -1.051 50.156 1.00 6.82 9.870 0.278 49.456 1.00 8.44 9.233 1.465 50.157 1.00 10.23 11.372 0.457 49.354 1.00 10.82 10.101 -3.500 50.160 1.00 7.68 11.267 -3.786 50.516 1.00 6.19 9.055 -4.208 50.514 1.00 9.15 9.226 -5.389 51.339 1.00 12.67 7.906 -6.055 51.525 1.00 15.98 6.902 -5.183 52.204 1.00 19.89 5.648 -5.941 52.477 1.00 22.91 5.674 -7.203 52.445 1.00 24.59 4.627 -5.286 52.726 1.00 26.87 10.169 -6.381 50.692 1.00 14.63 10.849 -7.147 51.409 1.00 12.25 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -229-

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1152 1154 1155 1156 1158 1159 1160 1161 1163 1164 1165 1166 1167 1170 1171 1172 1174 1175 1176 1177 1178 1179 1183 1184 1185 1187 1188 1189 1190 1191 1193 1194 1195 1197 1198 1199 1200 1202 1203 1204 1205 1206 1207 1208 1209 1211 1212 1213 1214 1215 1216 1217 1219 1220 1221 1222 N THR L 127 GA TH-R L 127 GB THR L 127 OG I THR L 127 CG2 THR L 127 C THR L 127 O THR L 127 N ASN L 128 GA ASN L 128 GB ASN L 128 CG ASN L 128 ODI ASN L 128 ND2 ASN L 128 C ASN L 128 0 ASN L 128 N LYS L 129 GA LYSL 129 GB LYS L 129 CG LYS L 129 CD LYS L 129 CE LYS L 129 NZ LYS L 129 C LYS L 129 0 LYS L 129 N ALA L 130 CA ALA L 130 GB ALA L 130 C ALA L 130 0 ALA L 130 N THR L 131 CA THR L 131 GB THR L 131 OG I THR L 131 CG2 TH-RL 131 C THR L 131 O THR L 131 N LEU L 132 CA LEU L 132 GB LEU L 132 CG LEU L 132 CD I LEU L 132 CD2 LEU L 132 C LEU L 132 0 LEU L 132 N VAL L 133 GA VAL L 133 GB VAL L 133 CG I VAL L 133 CG2 VAL L 133 C VAL L 133 O VAL L 133 N CYS L 134 CA CYS L 134 GB CYS L 134 SG GYS L 134 C CYS L 134 10. 177 -6.394 49.3 16 1.00 13.98 11.063 -7.308 48.538 1.00 13.13 10.565 -7.557 47.071 1.00 11.80 10.749 -6.384 46.266 1.00 10.21 9.095 -7.940 47.045 1.00 12.12 12.468 -6.773 48.455 1.00 12.72 13.278 -7.319 47.728 1.00 14.85 12.744 -5.701 49.209 1.00 13.49 14.053 -5.049 49.228 1.00 13.82 15.159 -6.035 49.674 1.00 19.63 15.148 -6.262 51.183 1.00 23.79 14.978 -7.388 51.646 1.00 26.72 15.329 -5.186 51.962 1.00 25.77 14.414 -4.367 47.901 1.00 14.19 15.611 -4.119 47.595 1.00 13.24 13.375 -4.018 47.146 1.00 17.87 13.534 -3.327 13.092 -4.229 13.737 -5.609 15.231 -5.502 15.855 -6.861 15.417 -7.440 45.875 44.705 44.662 44.540 44.340 43.042 12.686 -2.050 45.854 11.623 -1.980 46.448 13.173 -1.048 45.154 12.448 0.214 44.99S 12.977 1.267 45.964 12.572 0.727 43.545 13.691 0.988 43.056 11.412 0.808 42.863 11.349 1.323 41.522 10.665 0.346 40.546 1.00 18.00 1.00 22.35 1.00 24.95 1.00 28.22 1.00 30.22 1.00 34.30 1.00 16.78 1.00 15.40 1.00 16.40 1.00 15.30 1.00 10.48 1.00 13.30 1.00 13.88 1.00 10.24 1.00 8.65 1.00 9.65 11.277 -0.964 40.640 1.00 10.61 10.733 0.897 39.099 1.00 8.13 10.550 2.594 41.507 1.00 4.73 9.443 2.621 42.017 1.00 7.42 11.136 3.637 40.962 1.00 5.79 10.436 4.899 40.780 1.00 8.20 11.372 6.085 41.065 1.00 7.00 11.780 6.385 42.529 1.00 9.11 12.638 5.274 43.087 1.00 6.00 12.583 7.694 42.582 1.00 8.20 9.971 4.967 39.336 1.00 7.07 10.752 4.681 38.446 1.00 10.93 8.735 5.309 39.105 1.00 7.44 8.228 5.345 37.740 1.00 7.69 6.906 4.586 37.603 1.00 5.71 6.388 4.659 36.159 1.00 5.28 7.115 3.122 38.014 1.00 10.59 7.979 7.3 19 8.460 8.2 18 9.569 9.446 7.465 6.767 37.291 7.530 37.961 7.109 36.130 8.450 35.589 9.119 35.343 10.804 34.66, 8.302 34.290 1.00 8.68 1.00 8.54 1.00 12.17 1.00 9.67 1.00 8.40 1.00 10.83 1.00 9.67 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -230-

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1223 1224 1226 1227 1228 1230 1231 1232 1233 1235 1236 1237 1238 1239 1240 1241 1242- 1244 1245 1246 1248 1249 1250 1251 1253 1254 1255 1256 1257 1258 1259 1260 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1274 1275 1276 1277 1278 1279 1280 1281 1282 1284 1285 1286 1287 O CYS L 134 N THR L 135 CA THR L 135 CB THR L 135 OGI THR L 135 CG2 THR L 135 C THR L 135 O THR L 135 N ILE L 136 CA ILE L 136 GB ILE L 136 CG2 ILE L 136 CG I ILE L 136 CD ILE L 136 C ILE L 136 O ILE L 136 N- THR L 137 CA THR L 137 CB THR L 137 OGI THR L 137 CG2 THR L 137 C THR L 137 O THR L 137 N ASP L 138 CA ASP L 138 CB ASP L 138 CG ASP L 138 ODI ASP L 138 0D2 ASP L 138 C ASP L 138 0 ASP L 138 N PHE L 139 CA PHE L 139 CB PHE L 139 CG PHE L 139 GDl PHE L 139 CD2 PHE L 139 GEI PHE L 139 CE2 PHE L 139 CZ PHE L 139 C PHE L 139 O PHE L 139 N TYR L 140 CA TYR L 140 GB TYR L 140 CG TYR L 140 CD1I TYR L 140 CE I TYR L 140 GD2 TYR L 140 CE2 TYR L 140 GZ TYR L 140 OH TYR L 140 C TYR L 140 O TYR L 140 N PRO L 141 CD PRO L 141 8.017 7.705 33.364 1.00 10.89 6.209 8.737 34.238 1.00 6.29 5.480 8.651 33.029 1.00 5.35 4.031 8.177 33.248 1.00 5.71 3.243 9.196 33.888 1.00 11.96 4.020 6.904 34.103 1.00 2.00 5.549 9.988 32.324 1.00 9.71 5.820 11.015 32.958 1.00 11.41 5.440 9.989 31.002 1.00 9.98 5.696 11.237 30.220 1.00 11.09 7.171 11.270 29.677 1.00 12.20 7.447 12.606 28.973 1.00 10.90 8.185 11.008 30.796 1.00 10.97 9.585 10.663 30.291 1.00 11.49 4.750 11.230 29.030 1.00 10.64 4.856 10.351 28.213 1.00 11.08 3.811 12.165. 28.941 1.00 10.77 2.822 12.072 27.911 1.00 9.97 1.480 11.508 28.492 1.00 11.90 0.871 12.407 29.467 1.00 11.66 1.739 10.177 29.180 1.00 12.72 2.603 13.412 27.228 1.00 13.30 3.179 14.432 27.673 1.00 10.45 1.843 13.350 26.118 1.00 12.35 1.351 14.531 25.355 1.00 14.23 0.323 15.306 26.176 1.00 12.77 -0.780 14.436 26.702 1.00 16.64 -1.708 14.078 25.914 1.00 15.94 -0.734 14.100 27.912 1.00 16.10 2.413 15.502 24.881 1.00 12.96 2.186 16.705 24.905 1.00 13.42 3.568 15.011 24.444 1.00 15.33 4.597 5.991 6.464 6.004 7.387 6.444 7.829 15.917 15 .682 14.248 13 .382 13 .775 12.088 12.467 23.904 24.506 24.548 25.535 23.60 25.589 23.665 1.00 12.61 1.00 13.93 1.00 17.51 1.00 14.06 1.00 18.44 P1.00 15.91 1.00 17.97 1.00 19.08 1.00 14.58 1.00 13.97 1.00 14.53 7.354 11.618 24.659 4.685 15.810 22.403 4.391 14.757 21.835 5.010 16.951 21.763 5.2 19 3.929 4.150 4.110 4.355 4.443 4.691 4.639 4.842 17.022 17.256 17.200 15 .993 15.923 18.351 18.289 17.069 16.999 20,306 19.548 18.050 17.372 16.003 17.3 12 15.945 15.307 13 .958 1.00 15.96 1.00 9.65 1.00 17.09 1.00 18.26 1.00 18.78 1.00 17.33 1.00 17.98 1.00 19.92 1.00 21.97 6.148 18.174 20.045 1.00 14.90 5.8 15 19.264 20.460 1.00 17.79 7.336 18.004 19.364 1.00 17.44 8.342 19.079 19.203 1.00 18.49 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -23 1-

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1288 CA 1289 CB 1290 G PRO L 141 PRO L 141 PRO L 141 1291 1292 1293 1295 1296 1297 1298 1300 1301 1302 1303 1304 1305 1306 1308 1309 1310 1311 1312 1313 1314 1316 1317 1318 1320 1321 1322 1323 1325 1326 1327 1328 1329 1330 1331 1333 1334 1335 1336 1337 1338 1339 1340 1342 1343 1344 1345 1346 1347 1348 1349 1351 1352 PRO L 141 PRO L 141 GLY L 142 GLY L 142 GLY L 142 GLY L 142 VAL L 143 CA VAL L 143 GB3 VAL L 143 CG I VAL L 143 CG2 VAL L 143 C VAL L 143 O VAL L 143 N VAL L 144 CA VAL L 144 GB VAL L 144 CG I VAL L 144 CG2 VAL L 144 C VAL L 144 O VAL L 144 N TH-R L 145 CA THR L 145 CB THR L 145 OG I THR L 145 CG2 THR L 145 C THR L 145 O THR L 145 N VAL L 146 CA VAL L 146 GB3 VAL L 146 CG I VAL L 146 CG2 VAL L 146 C VAL L 146 O VAL L 146 N ASP L 147 CA ASP L 147 GB ASP L 147 CG ASP L 147 ODI ASP L 147 0D2 ASP L 147 C ASP L 147 O ASP L 147 N TRP L 148 CA TRP L 148 GB TRP L 148 CG TRP L 148 CD2 TRP L 148 CE2 TRP L 148 CE3 TRP L 148 CDI TRP L 148 NEI TRY L 148 CZ2 TRP L 148 CZ3 TRP L 148 7.877 16.736 18.791 1.00 16.51 9.278 17.128 18.347 1.00 16.41 9.148 18.569 18.067 1.00 18.35 7.979 15.574 19.770 1.00 17.49 8.111 15.777 20.988 1.00 16.25 7.960 14.373 19.221 1.00 16.47 8.127 13.182 20.027 1.00 17.96 9.568 12.873 20.379 1.00 17.11 10.011 11.740 20.287 1.00 20.37 10.332 13.846 20.753 1.00 17.91 11.674 13.548 21.201 1.00 20.37 12.750 13.989 20.189 1.00 25.23 12.526 15.434 19.776 1.00 27.03 14.139 13.811 20.807 1.00 23.81 11.937 14.194 22.555 1.00 20.36 11.696 15.394 22.719 1.00 18.56 12.421 13.375 23.518 1.00 18.00 12.729 13.837 24.885 1.00 18.09 11.586 13.520 25.905 1.00 15.31 10.361 14.336 25.624 1.00 13.05 11.246 12.034 25.879 1.00 15.08 13.952 13.124 25.398 1.00 17.23 14.204 11.987 24.997 1.00 15.86 14.747 13.803 26.217 1.00 16.98 15.794 13.116 26.930 1.00 17.36 17.242 13.734 26.774 1.00 22.21 17.616 14.518 27.914 1.00 22.36 17.364 14.570 25.512 1.00 19.06 15.373 13.105 28.394 1.00 19.55 14.797 14.085 28.864 1.00 15.45 15.581 11.966 29.070 1.00 19.67 15.178 11.799 30.468 1.00 17.75 14.336 10.511 30.665 1.00 15.39 14.047 10.262 32.148 1.00 16.28 13.047 10.641 29.918 1.00 12.45 16.425 11.702 31.322 17.336 10.964 30.998 16.464 12.470 32.388 17.595 12.483 33.267 18.330 13.834 33.1 13 19.078 13.955 31.783 1.00 18.57 1.00 20.82 1.00 16.64 1.00 16.87 1.00 22.38 1.00 25.15 20.155 13.339 31.665 1.00 25.53 18.579 14.656 30.862 1.00 24.06 17.111 12.297 34.702 1.00 13.63 16.206 13.007 35.146 1.00 17.40 17.692 11.353 35.403 1.00 12.32 17.296 11.059 36.799 1.00 8.34 17.205 16.011 14.73 5 13 .897 14.234 15 .894 14.636 12.570 12.921 9.517 37.013 8.871 36.393 8.685 37.020 8.085 36.079 8.974 38.312 8.383 35.122 7.923 34.955 7.753 36.354 8.645 38.604 1.00 7.75 1.00 9.41 1.00 7.75 1.00 9.98 1.00 11.38 1.00 5.30 1.00 10.25 1.00 10.62 1.00 8.84 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -232-

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1353 1354 1355 1356 1358 1359 1360 1361 1362 1363 1367 1368 1369 1371 1372 1373 1374 1375 1376 1377 1379 1380 1381 1382 1383 1384 1385 1386 1388 1389 1390 1391 1393 1394 1395 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1409 1410 1411 1412 1413 1414 1415 1417 1418 1419 CH2 TRP L 148 C TRP L 148 0 TRP L 148 N LYS L 149 CA LYS L 149 CB LYS L 149 CG LYS L 149 CD LYS L 149 CE LYS L 149 NZ LYS L 149 C LYS L 149 O LYS L 149 N VAL L 150 CA VAL L 150 CB VAL L 150 CG I VAL L 150 CG2 VAL L 150 C VAL L 150 0 VAL L 150 N ASP L 151 CA ASP L 151 CB ASP L 151 CG ASP L 151 ODI ASP L 151 OD2 ASP L 151 C ASPLI151 O ASP L 151 N GLY L 152 CA GLY L 152 C GLY L 152 O GLY L 152 N THR L 153 CA THR L 153 CB THR L 153 OG I THR L 153 CG2 THR L 153 C THR L 153 O THR L 153 N PRO L 154 CD PRO L 154 CA PRO L 154 CB PRO L 154 CG PRO L 154 C PRO L 154 O PRO L 154 N VAL L 155 CA VAL L 155 CB VAL L 155 CG I VAL L 155 CG2 VAL L 155 C VAL L 155 o VAL L 155 N THR L 156 CA THR L 156 CB THR L 156 OG I THR L 156 12.095 8.040 37.623 1.00 9.81 18.339 11.610 37.747 1.00 10.55 19.536 11.570 37.449 1.00 11.66 17.9 12 18.860 18.984 19.865 19.782 20.998 21.311 18.493 17.327 19.529 19.36: 19.87 20.31 18.76 20. 137 21.379 19.393 20.020 20.884 20.085 I2.107 38.895 1.00 10.12 12.586 14.117 14.477 15 .929 16.333 15.344 39.861 39.736 38.528 3 8. 126 37.272 36.170 1.00 10.24 1.00 9.85 1.00 15.84 1.00 20.45 1.00 25.03 1.00 26.83 12.114 41.261 1.00 9.83 11.939 41.568 1.00 8.42 11.821 42.045 1.00 12.70 3 11.400 43.445 1.00 13.13 19.958 43.597 1.00 14.08 1 9.690 45.000 1.00 9.65 .0 8.990 43.198 1.00 12.12 12.3 57 12.391 13.156 14. 166 13.5 16 12.908 44.381 44.371 45.184 46.056 47.141 48.292 1.00 13.82 1.00 11.33 1.00 15.72 1.00 13.64 1.00 17.87 1.00 18.72 18.851 13.014 48.304 1.00 17.99 20.701 12.320 49.195 1.00 20.12 20.841I 15.107 45.202 1.00 12.12 21.967 15.546 45.535 1.00 14.72 20.285 15.373 44.070 1.00 13.53 20.889 16.3 13 43.159 1.00 15.70 21.951 15.745 42.250 1.00 16.31 22.364 16.424 41.322 1.00 17.83 22.399 14.515 42.476 1.00 18.56 23.473 13.958 41.634 1.00 18.43 24.498 13.190 42.480 1.00 19.60 23.896 12.012 43.019 1.0025.85 24.964 14.055 43.650 1.00 23.47 22.904 2 1.899 23.516 24.730 23.038 23 .865 13.094 40.4821 12.393 40.614 13.173 39.2991 13.967 38.997 12.424 38.120 13.030 36.987 1.00 18.68 1.00 18.23 1.00 18.73 1.00 19.95 1.00 18.94 1.00 18.59 25.150 13.360 37.688 1.00 18.89 23.196 10.914 38.253 1.00 15.33 24.232 10.443 38.662 1.00 16.30 22.150 10.147 37.978 1.00 16.59 22.323 8.703 38.040 1.00 19.40 21.065 7.962 38.617 1.00 19.34 20.124 8.947 39.276 1.00 18.37 20.353 7.132 37.558 1.00 18.74 22.760 8.141 36.641 1.00 21.02 22.397 8.681 35.565 1.00 19.02 23.606 7.121 36.664 1.00 22.42 24.093 6.532 35.438 1.0023.32 25.579 6.770 35.317 1.00 23.16 26.227 6.276 36.494 1.00 25.01 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -2 33 3-

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1421 1422 1423 1424 1426 1427 1428 1429 1430 1431 1434 1435 1436 1438 1439 1440 1441 1443 1444 1445 1446 1447 1448 1449 1450 1452 1453 1454 1455 1456 1457 1458 1459 1460 1462 1463 1464 1466 1467 1468 1469 1471 1472 1473 1475 1476 1477 1478 1480 1481 1482 1483 1484 1485 1486 1487 CG2 THR L 156 C THR L 156 O THR L 156 N GLN L 157 GA GLN L 157 GB GLN L 157 CG GLN L 157 GD GLN L 157 OEI GLN L 157 NE2 GLN L 157 C GLN L 157 O GLN L 157 N GLY L 158 CA GLY L 158 C GLY L 158 O GLY L 158 N MET L 159 CA MET L 159 GB MET L 159 GG MET L 159 SD MET L 159 CE MET L 159 C MET L 159 O MET L 159 N GLU L 160 GA GLU L 160 GB GLU L 160 CG GLU L 160 GD GLU L 160 OE1 GLU L 160 0E2 GLU L 160 C GLU L 160 O GLU L 160 N THR L 161 GA TH-R L 161 GB THR L 161 OG I THR L 161 GG2 THR L 161 G THR L161 O TH-R L 161 N THR L 162 GA THR L 162 GB THR L 162 OG I THR L 162 GG2 THR L 162 G THR L 162 O TH-R L 162 N ALA L 163 GA ALA L 163 GB ALA L 163 G ALA L 163 O ALA L 163 N PRO L 164 GD PRO L 164 GA PRO L 164 GB PRO L 164 25.845 8.249 35.18 1 1.00 25.87 23.858 5.049 35.421 1.00 25.17 24.327 4.357 34.533 1.00 28.73 23.119 4.554 36.376 1.00 23.46 22.909 3.152 36.465 1.00 23.50 23.954 2.603 37.389 1.00 29.55 24.032 1.102 37.399 1.00 37.55 25.281 0.639 38.106 1.00 43.33 25.750 1.288 39.060 1.00 43.65 25.845 -0.472 37.63 1 1.00 45.54 21.525 2.871 36.994 1.00 19.92 21-025 3-63 1 37.778 1.00 18.81 20.895 19.569 18 .397 17.281 18.630 17.539 17.8 10 18.833 20.522 21.030 17.277 18.188 16.026 15.670 15.366 14.501 15.230 16.4&~ 14.551 14.491 13.446 14.667 13.611 14. 163 14.62' 13.1 0 13.091 13 .859 11.777 11.163 9.768 8.86f 9.880 11.085 11.083 11.071 11.05~ 1 1.43z 1.817 36.526 1.00 18.99 1.471 37.010 1.00 20.19 2.250 36.382 1.00 22.36 2.099 36.815 1.00 22.31 3.080 35.374 1.00 24.81 3.802 34.741 1.00 22.88 5.312 34.684 1.00 23.15 5.795 33.687 1.00 26.34 5.748 34.304 1.00 34.44 4.165 33.643 1.00 31.53 3.230 33.351 1.00 23.01 2.833 32.662 1.00 24.49 3.169 32.960 1.00 19.49 2.591 3 1.710 1.00 19.70 1.107 31.939 1.00 21.50 0.431 30.913 1.00 24.34 0.049 29.644 1.00 30.12 -0.184 29.733 1.00 28.32 -0.02 1 28.55 1 1.00 30.69 7 7 3.326 3.366 3.908 4.715 6.137 6.74 7.02 3 1.156 1.00 19.64 31.785 1.00 18.31 29.959 1.00 20.21 29.300 1.00 18.39 28.972 1.00 19.35 1 30.188 1.00 15.43 5 28.342 1.00 13.84 4.047 28.007 1.00 18.90 3.391 27.292 1.00 18.53 4.198 27.738 1.00 17.02 3.603 26.573 1.00 14.46 3.023 26.890 1.00 9.31 4.067 27.336 1.00 8.44 1.940 27.965 1.00 8.50 4.614 25.421 1.00 15.09 5.834 25.624 1.00 14.93 4.110 24.200 1.00 12.96 4.983 23.052 1.00 10.76 4.212 21.768 1.00 15.08 9.719 5.567 22.921 1.00 8.59 8.749 4.856 23.017 1.00 11.96 9.632 6.894 22.721 1.00 11.37 10.762 7.849 22.597 1.00 12.89 8.352 7.578 22.587 1.00 11.21 8.746 8.956 22.069 1.00 11.04 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -234-

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1488 1489 1490 1491 1493 1494 1495 '497 1498 1499 1501 1502 1503 1504 1505 1506 1510 1511 1512 1514 1515 1516 1517 1518 1519 1522 1523 1524 1526 1527 1528 1530 1531 1532 1534 1535 1536 1537 1538 1541 1542 1543 1545 1546 1547 1548 1549 1552 GG PRO L 164 C PRO L 164 O PRO L 164 N SER L 165 CA SER L 165 CB SER L 165 OG SER L 165 C SER L 165 O SER L 165 N LYS L 166 CA LYS L 166 GB LYS L 166 CG LYS L 166 CD LYS L 166 CE LYS L 166 NZ LYS L 166 C LYS L 166 O LYS L 166 N GLN L 167 CA GLN L 167 GB GLN L 167 CG GLN L 167 CD GLN L 167 OEI GLN L 167 NE2 GLN L 167 C GLN L 167 O GLN L 167 N SER L 168 CA SER L 168 GB SER L 168 OG SER L 168 C SER L 168 0 SER L 168 N ASN L 169- CA ASN L 169 GB ASN L 169 CG ASN L 169 OD I ASN L 169 ND2 ASN L 169 C ASN L 169 0 ASN L 169 N ASN L 170 CA ASN L 170 GB ASN L 170 CG ASN L 170 ODI ASN L 170 ND2 ASN L 170 C ASN L 170 10.047 9.160 22.761 1.00 11.07 7.488 6 7.986 6 6.221 6 5.334 4.889 3.841I 4.201 7 3.927 7 3.588 7 2.573 2.382 2.308 2.292 2.623 1 2.568 1.276 7 0.893 6 0.614 -0.716 -0.983 0.047 -0.193 0.488 -1.157 -1.702 -1.347 -2.929 -3.955 -5.305 -5.428 -3.996 1 -4.401 1 -3-.579. 1 .825 ;.130 .878 6.188 4.810 4.922 .099 '.920 .018 7.988 8.0 12 9.398 9.300 I0.640 10.57 '.704 .547 8.770 2 2 2 2 2 1.632 :0.746 1.829 20.925 21.470 22.407 0.724 1.584 9.594 1.00 12.84 1.00 17.44 1.00 14.17 1.00 16.08 1.00 17.01 1.00 22.35 1.00 15.78 1.00 15.19 1.00 17.84 19.257 1.00 19.88 17.758 1.00 22.34 17.150 1.0021.36 15.619 1.00 25.05 14.981 0.01 22.27 13.495 0.01 22.15 19.925 1.00 21.48 20.063 1.00 23.82 20.372 1.00 20.46 8.658 9.729 9.821 10.992 11.145 1 1.83 20.935 21.969 23.080 24.01 25.06 123.67 8.865 19.814 9.393 18.782 1.494 20.029 1.00 19.43 1.00 19.09 F1.00 13.91 7 1.00 12.43 6 1.0012.78 0 1.00 12.35 1.00 20.58 1.00 19.43 1.00 24.20 1.00 28.22 1.00 29.04 1.00 34.62 1.00 30.48 1.00 34.63 1,.00 26.12 8.647 8.283 8.880 0.085 0.335 1.035 19.009 19.615 20.904 18.468 17.308 19.279 -3.644 12.398 18.848 1.00 25.93 -4.066 13.329 19.982 1.00 29.63 -3.125 13.386 21.158 1.00 29.04 -2.107 12.704 21.219 1.00 31.37 -3.479 14.214 22.099 1.00 31.92 -2.351 12.815 18.283 1.00 25.86 -2.052 13.991 18.186 1.00 26.70 -1.578 11.847 17.927 1.00 23.96 -0.3 14 12.085 17.286 1.00 23.68 -0.543 12.718 15.919 1.00 25.27 -1.095 11.647 14.987 1.0028.14 -0.390 10.682 14.651 1.00 30.35 -2.362 11.765 14.614 1.00 29.66 0.690 12.837 18.108 1.00 22.90 1.720 13.248 17.607 1.00 25.60 0.407 13.049 19.361 1.00 21.22 1553 1554 1556 1557 1558 1559 1560 ASN L 170 LYS L 171 LYS L 171 LYS L 171 LYS L 171 LYS L 171 LYS L 171 1.452 0.888 0.207 -0.340 -1.277 -1.526 13.524 20.244 14.296 21.429 15.595 21.1 12 16.198 22.407 17.358 22.132 18.187 23.347 1.00 19.04 1.00 17.22 1.00 17.62 1.00 15.1 1 1.00 18.27 1.00 14.34 ATOM 1561 NZ LYS L 171 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -2 3

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1565 C LYS L 171 1566 0 LYS L 171 1567 N TYR L 172 1569 CA TYR L 172 1570 GB TYR L 172 1571 CG TYR L 172 1572 CD I TYR L 172 1573 GEI TYR L 172 1574 CD2 TYR L 172 1575 CE2 TYR L 172 1576 CZ TYR L 172 1577 OH TYR L 172 1579 C TYR L 172 1580 0 TYR L 172 1581 N MET L 173 1583 CA MET L 173 1584 GB MET L 173 1585 GG MET L 173 1586 SD MET L 173 1587 CE MET L 173 1588 C MET L 173 1589 0 MET L 173 1590 N ALA L 174 1592 CA ALA L 174 1593 GB ALA L 174 1594 C ALA L 174 1595 0 ALA L 174 1596 N SER L 175 1598 GA SER L 175 1599 GB SER L 175 1600 OG SER L 175 1602 C SER L 175 1603 0 SER L 175 1604 N SER L 176 1606 CA SER L 176 1607 GB SER L 176 1608 OG SER L 176 1610 C SER L 176 1611 0 SER L 176 1612 N TYR L 177 1614 CA TYR L 177 1615 GB TYR L 177 1616 CG TYR L 177 1617 CD] TYR L 177 1618 CEI TYR L 177 1619 CD2 TYR L 177 1620 CE2 TYR L 177 1621 CZ TYRLI177 1622 OH TYR L 177 1624 C TYR L 177 1625 0 TYR L 177 1626 N LEU L 178 1628 CA LEU L 178 1629 GB LEU L 178 1630 CG LEU L 178 1631 CD1 LEU L 178 2.140 1 1.728 1 3.132 1 3.863 5.301 5.451 5.218 5.377 5.836 5.995 5.773 5.968 2.247 20.744 1.156 20.373 2.353 21.586 11.178 21.97( 11.331 21.51( 11.261 12.372 12.281 10.071 9.974 11.070 10.945 20.022 19.19 17.81: 19.42 18.053 17.242 15.871 1.00 17.36 1.00 17.98 1.00 14.79 1.00 14.85 1.00 15.82 1.00 17.24 6 1.00 15.15 2 1.00 18.45 7 1.00 17.80 1.00 20.12 1.00 18.23 11.00 13.35 3.838 10.907 23.461 1.00 15.41 3.585 11.820 24.271 1.00 14.17 4.111 4.195 2.927 2.767 1.450 0.045 5.455 6.005 5.935 7.131 8.410 7.164 6.371 8.055 8.163 7.275 7.633 9.606 10.408 9.975 11.313 12. 179 13 .547 11.221 10.237 12.212 12.235 12.051 10.695 9.63( 8.371 10.46 9.2 12 8.169 6.901 13 .560 14.563 13.558 14.76' 14.W9 1 6.22 7 6 5 6 p.639 23.811 9.241 25.19: 8.498 25.60( 7.121 24.97: 6.149 25.71S 6.910 24.99: .386 25.429 v.778 24.500 .354 26.658 7.594 27.00' 8.325 26.53,' '.383 28.521 .983 29.240 .519 28.984 6.231 3 0.404 5.031 30.782 3.838 30.073 .949 30.777 i.513 29.919 .223 32.048 1.00 13.34 Z 1.00 9.55 )1.00 10.24 3 1.00 15.16 S1.00 20.11 1.00 12.86 1.00 10.38 1.00 10.40 1.00 7.39 5 1.00 7.66 1.00 4.47 1.00 8.50 1.00 7.42 1.00 8.85 1.00 9.69 1.00 8.09 1.00 12.41 1.00 10.11 1.00 9.58 1.00 6.07 5.918 32.495 1.00 3.46 7.152 32.471 1.00 2.00 6.852 32.684 1.00 2.00 5.305 33.892 1.00 5.39 5.487 34.558 1.00 7.78 4.513 34.237 1.00 6.76 3.758 35.455 1.00 8.12 2.273 35.151 1.00 6.07 1.871 34.600 1.00 6.17 1.577 35.457 1.00 6.94 1.231 34.938 1.00 8.14 1 1.799 33.224 1.00 6.52 1.459 32.716 1.00 7.03 1.178 33.568 1.00 6.45 0.894 33.061 1.00 6.11 3.886 36.100 1.00 6.87 3.836 35.428 1.00 9.13 4.034 37.400 1.00 6.48 1 3.993 38.156 1.00 6.11 )5.312 38.847 1.00 6.46 8 5.448 39.722 1.00 7.03 17.496 5.055 38.993 1.00 10.30 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -23 6-

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1632 1633 1634 1635 1637 1638 1639 1641 1642 1643 1644 1646 1647 1648 1649 1650 1651 1652 1653 1655 1656 1657 1659 1660 1661 1662 1664 1665 1666 1667 1668 1670 1671 1672 1673 1674 1676 1677 1680 1683 1684 1685 1687 1688 1689 1690 1691 1693 1694 1695 1696 1697 1698 1 699 1 700 1702 CD2 LEU L 178 C LEU L 178 0 LEU L 178 N TH-R L 179 CA THR L 179 GB TH-R L 179 OGI THR L 179 CG2 THR L 179 C THR L 179 O THR L 179 N LEU L 180 CA LEU L 180 GB LEU L 180 CG LEU L 180 CD I LEU L 180 C132LEU L 180 C LEU L 180 0 LEU L 180 N THR L 181 CA THR L 181 CB THR L 181 OG I THR L 181 CG2 THR L 181 C THR L 181 0 THR L 181 16.308 6.878 40.219 1.00 13.82 14.618 2.885 39.156 1.00 8.35 13.687 2.862 39.902 1.00 10.42 15.550 1.969 39.130 1.00 11.56 15.522 0.802 39.963 1.00 13.47 15.703 -0.456 39.096 1.00 15.12 14.558 -0.594 38.292 1.00 14.73 15.847 -1.722 39.940 1.00 19.56 16.613 17.808 16. 177 17.021 16.614 16.667 0.903 1.133 0.755 0.929 2.2 10 3.566 4 1.008 40.693 42.248 43 .383 44.155 43.424 1.00 1.00 1.00 1.00 1.00 1.00 16.41 15.41 16.98 17.38 17.62 18.66 16.074 4.662 44.300 1.00 15.82 18.108 3.926 43.067 1.00 19.60 16.793 -0.217 44.300 1.00 15.89 15.742 -0.853 44.241 1.00 20.00 17.766 -0.482 45.130 1.00 16.39 17.562 -1.407 46.238 1.00 16.84 18.888 -1.803 46.924 1.00 15.01 19.566 -0.615 47.398 1.00 18.96 19.791 -2.578 45.975 1.00 16.62 16.753 -0.634 47.265 1.00 14.44 16.705 0.607 47.201 1.00 16.04 16.120 -1.307 48.192 1.00 15.12 N ALA L 182 CA ALA L 182 GB ALA L 182 C ALA L 182 0 ALA L 182 N ARO L 183 CA ARG L 183 GB ARG L 183 CG ARG L 183 CD ARG L 183 NE ARG L 183 CZ ARG L 183 NH I ARG L 183 NH2 ARG L 183 C ARG L 183 O ARG L 183 N ALA L 184 GA ALA L 184 GB ALA L 184 C ALA L 184 O ALA L 184 N TRP L 185 CA TRP L 185 GB TRP L 185 GG TRP L 185 GD2 TRP L 185 CE2 TRP L 185 CE3 TRP L 185 CDI TRP L 185 NEI TRP L 185 CZ2 TRP L 185 15.421 14.687 16.427 16.111 17.645 18.623 19.894 2 1.080 22. 102 23.465 24.403 -0.582 49.24S -1.564 50.157 0.289 50.076 1.422 50.478 .0.219 50.307 I1.00 13.02 1.00 13.78 1.00 14.39 1.00 16.28 1.00 14.52 0.535 -0.287 0.527 -0.351 0.263 -0.026 51.069 51.295 51.825 52.53 8 52.582 53.535 1.00 16.24 1.00 19.45 1.00 24.50 1.00 29.62 1.00 35.27 1.00 35.81 25.633 0.509 53.470 1.00 35.30 24.098 -0.817 54.555 1.00 36.43 18.930 18.887 19. 195 19.460 19.774 18.248 18.3 83 17.057 15.851 14.630 13.402 12.8 18 11.622 13.177 12.572 11.511 10.783 1.869 2.903 1.857 3.076 2.735 4.012 5.227 3.453 4.264 3.391 4.062 5.26 5.50( 6.W4 3.63w 4.50: 6.58: 50.400 51.049 49.091 48.392 46.955 48.496 48.667 48.408 48.467 48.243 48.687 1 48.138 48.840 47.109 9 49.683 3 49.757 I48.556 1.00 18.26 1.00 19.19 1.00 16.18 1.00 10.91 1.00 9.98 1.00 12.19 1.00 11.01 1.00 10.53 1.00 11.80 1.00 11.64 1.00 9.64 1.00 14.47 1.00 14.89 1.00 14.90 11.00 15.33 1.00 15.12 1.00 15.58 SUBSTITIUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 *237-

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1703 1704 1705 1706 1707 1709 1710 1711 1712 1713 1714 1715 1716 1717 1719 1720 1721 1722 1723 1725 1726 1729 1732 1733 1734.

1736 1737 1738 1739 1740 1742 1743 1745 1746 1747 1749 1750 1751 1753 1754 1755 1757 1758 1759 1761 1762 1763 1765 1766 1767 1768 1769 1770 1771 1772 1773 CZ3 TRP L 185 CH2 TRP L 185 C TRP L 185 0 TRP L 185 N GLU L 186 CA GLU L 186 GB GLU L 186 CG GLU L 186 GD GLU L 186 OEI GLU L 186 0E2 GLU L 186 C GLU L 186 O GLU L 186 N ARG L 187 CA ARG L 187 GB ARG L 187 CG ARG L 187 CD ARG L 187 NE ARG L 187 CZ ARG L 187 [2.349 7.209 46.821I 1.00 12.52 11. 162 7.419 47.544 1.00 12.84 15.693 5.024 49.798 1.00 16.85 NH I ARG L 187 NH2 ARG L 187 C ARG L 187 O ARG L 187 N HISLI188 GA HIS L 188 GB HIS L 188 CG HIS L 188 CD2 HIS L 188 NDI HIS L 188 GEl HIS L 188 NE2 HIS L 188 C HIS L 188 O HIS L 188 N SER L 189 GA SER L 189 GB SER L 189 OG SER L 189 G SERLI189 0 SER L 189 N SER L 190 GA SER L 190 GB SER L 190 OG SER L 190 G SER L 190 O SER L 190 N TYR L 191 GA TYR L 191 GB TYR L 191 GG TYR L 191 GD I TYR L 191 GEl TYR L 191 GD2 TYR L 191 CE2 TYR L 191 GZ TYR L 191 OH TYR L 191 15.351 15.942 15.75' 15.76 14.96: 15.28 16.18 14.66 16.871 16.73 3 17.991 19.12 20.37' 21.57 22.68 23.33 24.664 25.2: 25.4: 19.089 19.798 18.281 18.247 18.559 19.880 20.26' 21.06( 22.118 21 .64( 16.893 15.897 16.855 15.58~ 15.79( 16.94: 15.03 8 13 .827 15.942 15.55~ 16.421 15.88.

15 .684 16.726 14.629 14.62 13.87 14.56 15.64 16.3( 14.2 14.9' 15.97 16.7' 6 7 7 2 8 3 3 4.979 3.927 2.655 1.566 1.799 0.485 52.223 53.332 53.073 54.110 54.944 54.086 1.00 19.08 1.00 21.77 1.00 25.99 0.50 26.59 0.50 23.57 0.50 23 .36 5.975 52.53 7 1.00 20.25 6.824 53.421 1.00 20.91 5.852 5 1.861 1.00 18.94 9 6.651 52.216 1.00 18.58 6 5.949 51.760 1.00 20.96 4 6.84 8 51.702 1.0027.24 7 6.156 50.972 1.0036.91 9 5.146 51.793 1.0039.36 0 5.032 51.834 1.0042.54 3 1 4.124 52.607 1.00 45.47 15 5.827 51.081 1.0046.06 8.077 5 1.671 1.00 18.28 8.946 52.176 1.00 20.00 8.333 50.647 1.00 17.48 9.674 50.027 1.00 16.15 9.585 48.486 1.00 13.42 8.962 48.214 1.00 14.37 7 7.658 48.229 1.00 15.01 0 9.680 48.221 1.00 14.95 18.897 48.281 1.00 13.98 7.663 48.299 1.00 15.86 10.318 50.255 1.00 16.60 9.614 50.431 1.00 18.56 11.660 50.285 1.00 18.06 7 12.384 50.467 1.00 17.30 13.568 51.425 1.00 20.51 3 14.314 51.086 1.00 18.48 12.891 49.144 1.00 18.08 12.891 48.917 1.00 21.50 13.272 48.248 1.00 17.95 7 13.876 46.968 1.00 17.18 8 15.100 46.714 1.00 14.84 4 15.885 45.679 1.00 24.95 12.922 45.798 1.00 15.72 12.282 45.606 1.00 16.39 412.845 45.031 1.00 15.74 .222 49.809 1.00 15.42 ,.343 50.918 1.00 16.92 '3 8 2 31 17 19 2 I0 12.054 43.793 10.730 44.016 9.836 45.023 9.008 44.611 8.219 45.503 9.856 46.395 9.060 47.302 8.245 46.835 7.505 47.709 1.00 18.47 1.00 20.26 1.00 20.87 1.00 23.39 1.0022.95 1.00 24.18 1.0026.25 1.0026.73 1.00 30.08 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -238-

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1775 1776 1777 1779 1780 1781 1783 1784 1785 1787 1788 1789 1790 1791 1792 1794 1795 1796 1797 1798 1799 1802 1803 1804 1806 1807 1808 1809 1810 1811 1812 1814 1815 1816 1818 1819 1820 1821 1823 1824 1825 1826 1827 1829 1830 1832 1833 1834 1836 1837 1838 1839 1840 1841 1842 1843 C TYR L 191 0 TYR L 191 N SER L 192 GA SER L 192 GB SER L 192 OG SER L 192 C SER L 192 O SER L 192 N GYS L 193 GA GYS L 193 GB GYS L 193 SG CYS L 193 C GYS L 193 O CYS L 193 N GLN L 194 GA GLN L 194 GB GLN L 194 CG GLN L 194 GD GLN L 194 OEI GLN L 194 NE2 GLN L 194 C GLN L 194 O GLN L 194 N VAL L 195 GA VAL L 195 GB VAL L 195 CGI VAL L 195 GG2 VAL L 195 C VAL L 195 0 VAL L 195 N THR L 196 GA THR L 196 GB THR L 196 OG I THR L 196 GG2 THR L 196 C THR L 196 O THR L 196 N HIS L 197 GA ISL 197 CB HIS L 197 CG HIS L 197 GD2 HIS L 197 NDI HIS L 197 GEl HIS L 197 NE2 HIS L 197 C HIS L 197 O HIS L 197 N GLU L 198 GA GLU L 198 GB GLU L 198 CG GLU L 198 GD GLU L 198 OEI GLU L 198 0E2 GLU L 198 C GLU L 198 0 GLU L 198 13, 939~ 12.923 14.477 13.909 14.734 14. 167 13.938 14.958 12.839 12.832 11.604 11.540 12.834 11.918 13 .849 13.93 15.221 15.47 16.70' 16.91 17.53 12.880 13 .505 12.883 13.741 15.031I 15.951 13. 135 12.641 13.208 12.817 11.985 11.360 14.075 14.867 14.261 6 15.48 16.20~ 1 16.45: 4 17.28: 3 17.82 8 17.39 42.683 42.929 4 1.464 40.451 40.432 39.536 39.071 38.661 38.359 36.950 36.621 I34.913 36.093 36.192 35.247 5 34.45( 34.730 3 36.18: 2 36.39: .8 37.48 '2 35.35 13.873 15.200 32.978 14.730 14.526 32.449 12.867 15.763 32.335 12.608 15.511 30.93 11.165 15.065 30.77( 10.866 14.807 29.31 10.902 13.839 31.64 12.823 16.764 30.072 12.012 17.702 30.111 13.904 16.763 29.295 14.192 17.876 28.375 15.716 17.992 28.17( 16.349 18.183 29.44 16.071 19.156 27.27 1.00 17.55 1.00 14.74 1.00 16.33 1.00 15.90 1.00 18.03 1.00 23.10 1.00 12.29 1.00 14.68 1.00 11.59 I1.00 14.23 1.00 15.78 1.00 15.09 1.00 12.46 1.00 14.42 1.00 14.04 1.00 14.30 I1.00 20.47 1.00 26.89 1.00 33.09 8 1.00 36.67 2 1.00 36.22 1.00 13.96 1.00 11.43 1.00 13.39 S 1.00 15.15 1.00 13.26 1 1.00 12.28 3 1.00 8.74 1.00 16.35 1.00 15.34 1.00 16.92 S1.00 15.93 1.00 18.12 3 1.00 22.55 '3 1.00 21.24 1.00 16.18 1.00 14.99 1.00 14.43 1.00 13.60 1.00 12.56 1.00 9.47 1.00 8.75 1.00 13.69 1.00 10.65 1.00 13.24 1.00 19.15 13 .507 13.746 12.638 11.923 10.429 9.581 9.549 8.492 7.842 8.472 12.084 17.647 27.035 16.598 26.400 18.625 26.619 18.563 25.348 18.345 25.566 18.336 24.308 17.479 23.275 19.191 24.088 18.873 22.994 17.842 22.506 19.882 24.607 11.393 20.882 24.950 1.0021.46 12.900 19.865 23.560 1.00 19.88 13.180 11.899 11.076 11.425 12.3 87 10.725 21.058 2 1.642 20.681 20.689 19.979 2 1.393 22.766 22. 147 2 1.322 19-856 19.468 19.086 1.00 23.30 1.00 25.45 1.00 25.96 1.00 29.67 1.00 31.64 1.00 27.15 1.3.834 22.126 23.630 1.00 25.19 13.366 23.251 23.670 1.00 25.37 SUBSTIT1UTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -239-

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1844 1846 1847 1848 1849 1851 1852 1853 1854 1855 1857 1858 1860 1861 1862 1864 1865 1866 1868 1869 1870 1871 1873 1874 1875 1876 1877 1878 1879 1881 1882 1883 1884 1885 1886 1887 1888 1889 1891 1892 1893 1 894 1 895 1 896 1 90( 1901 1 90: 1901 1 90~ 1 90( 1901 190' 1914 191 191: 191

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GLY L 199 GLY L 199 GLY L 199 GLY L 199 HIS L 200 HIS L 200 1 HIS L 200 14.863 21.742 24.369 1.00 26.71 15.636 22.709 25.110 1.00 28.67 15.019 23.191 26.406 1.00 30.20 15.623 24.028 27.078 1.00 31.36 13.825 22.693 26.755 1.00 29.3 1 CG HIS L 200 GD2 HIS L200 NDI HIS L 200 GE I HIS L 200 NE2 HIS L200 C HIS L200 0 HIS L 200 N THRL 201 CA THR L 201 GB3 THR L 201 OG I THRL 201 GG2 THR L 201 C THRL 201 0 THRL 201 N VALL 202 CA VALL 202 GB VAL L 202 CG I VALL 202 GG2 VAL L 202 C VALL 202 O VALL 202 N GLU L203 CA GLUL 203 GB GLUL 203 CG GLUL 203 CD GLUL 203 OE I GLU L203 0E2 GLU L 203 C GLU L203 0 GLU L203 N LYSL 204 13. 168 11.793 11.620 12.5 17 10.401 10.537 11.811 23. 108 23.766 24.410 24.952 24.456 24.971 25.274 27.996 1.00 29.70 27.747 1.00 34.13 26.399 1.0042.18 25.533 1.00 44.52 25.729 1.00 45.60 24.507 1 .00 46.26 24.385 1 .00 46.19 12.960 21.888 28.849 1.00 27.60 12.335 20.927 28.385 1.00 27.65 13.457 21.938 30.084 1.00 27.03 13.372 20.796 30.993 1.00 25.96 14.635 20.732 31.874 1.00 22.54 15.758 20.710 31.032 1.00 21.22 14.693 19.477 32.724 1.00 22.94 12.108 20.846 31.863 1.00 26.78 11.847 21.857 32.522 1.00 29.53 11.279 19.777 31.789 1.0025.81 10.124 19.623 32.694 1.00 22.79 8.881 19.138 31.929 1.0024.16 7.668 19.067 32.862 1.00 24.52 8.612 20.091 30.773 1.00 24.14 10.507 18.598 33.784 1.0021.74 10.960 17.5 19 33.480 1.00 19.01 10.340 18.934 35.055 1.0020.40 10.807 18.063 36.086 1.00 19.67 12.045 18.700 36.717 1.00 22.14 12.600 17.919 37.883 1.0027.78 13.320 18.803 38.886 0.50 30.15 14.564 18.934 38.777 0.50 30.52 12.636 19.369 39.785 0.50 30.93 5 6 2 3 4 LYSL 204 LYS L 204 iLYSL 204 LYSL 204 LYS L 204 LYSL 204 LYS L 204 LYSL 204 SERL 205 SER L205 1 SERL 205 SERL 205 SER L 205 SER L 205 LEU L 206 LEUL 206 3 LEUL 206 3 LEU L206 9.760 8.894 9.814 9.046 7.953 6.869 6.405 5.248 4.040 17.754 37.162 18.569 37.477 16.550 37.679 16.210 15.262 15.9 15 17. 166 17.766 16.962 38.837 38.527 37.724 38.415 37.666 37.885 1.00 18.69 1.00 19.41 1.00 16.36 1.00 14.59 1.00 15.55 1.00 21.54 1.00 21.69 1.00 22.39 1.00 20.85 9.977 15.621 39.853 1.00 15.55 11.004 14.995 39.505 1.00 13.34 9.650 15.852 41.124 1.00 17.28 10.5 12 15.428 42.198 1.00 16.96 11.296 16.622 42.760 1.00 18.69 12.404 16.972 41.916 1.00 25.46 9.722 14.826 43.299 1.00 16.29 8.568 15.117 43.445 1.00 12.40 10.389 13.967 44.035 1.00 17.28 9.856 13.360 45.233 1.00 20.60 9.911 11.825 45.136 1.00 18.66 9.048 11.160 44,061 1.00 17.51 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCTIGB98/02542 -240-

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1915 1916 1917 1918 1919 1921 1922 1923 1925 1926 1927 1929 1930 1931 1932 1933 1935 1936 1939 1942 1943 1944 1945 1946 1947 1950 1952 1953 1955 1956 1957 1958 1959 1960 1961 1963 1964 1965 1966 1967 1968 1971 1972 1973 1975 1976 1977 1978 1979 1980 1981 1982 1 984 1 985 1 986 1 987 -DI LEU L206 :D2 LEU L 206 LEU L206 )LEUL 206 1, SER L207 :A SER L207 ZB SER L207 SER L 207 ZSERL 207 0 SERL 207 N ARG L208 CA ARG L 208 CB ARG L208 CG ARG L 208 CD ARG L208 NE ARG L208 CZ ARG L 208 NH I ARC L 208 NH2 ARG L 208 C ARG L 208 OTI ARG L 208 OT2 ARGL 208 CB ALA H I C ALAI-H I O ALA H I N ALA H I CA ALA H I N. VAL H 2 CA VAL H 2 CB VAL-H 2 CGI VALH 2 CG2VALH 2 C VALH 2 O VALH 2 N GLNI-H 3 CA GLN H 3 CB GLN H 3 CG GLN H 3 CD GLN H 3 OE1 GLN H 3 NE2 GLN H 3 C GLN H 3 O GLN H 3 N LEU H 4 CA LEU H 4 CB LEU H 4 CG LEU H 4 CDI LEU H 4 CD2 LEUI-H 4 C LEU H 4 O LEU H 4 N GLN H 5 CA GLN H 5 CB GLN H 5 ~CGGLN H 5 ~CDGLN H 5 9.516 9.738 43.844 1.00 19.23 7.572 11.192 44.444 1.00 16.04 10.746 13.776 46.393 1.00 22.29 11.965 13.812 46.254 1.0020.72 10.140 14.155 47.487 1.00 26.92 10.896 14.355 48.713 1.00 33.08 10.498 15.640 49.434 1.00 32.95 11.247 15.787 50.628 1.00 35.61 10.579 13.157 49.602 1.00 35.86 9.404 12.760 49.734 1.00 38.31 11.601 12.563 50.163 1.00 36.32 11.422 11.391 50.979 1.0036.19 12.255 10.230 50.361 1.00 33.25 11.930 8.860 50.912 1.00 31.97 13.184 8.107 51.300 1.00 32.82 13.02 1 7.329 52.540 1.00 37.28 13.846 7.478 53.597 1.0043.16 13.703 6.735 54.711 1.0043.30 14.811 8.395 53.547 1.0045.46 11.840 11.779 52.420 1.0037.35 12.794 11.173 52.989 1.00 38.30 11.231 12.763 52.940 1.00 37.56 -0.820 -5.033 -4.579 1.00 35.02 1.166 -6.495 -4.905 1.00 32.62 0.782 -7.582 -4.499 1.00 32.59 -0.539 -6.302 -6.690 1.00 37.70 0.184 -5.565 -5.595 1.00 34.79 2.419 -6.0,48 -4.790 1.00 29.87 3.463 -6.829 -4.153 1.00 28.68 4.803 -6.111 -4.242 1.00 27.24 5.901 -6.933 -3.589 1.00 30.14 5.116 -5.835 -5.701 1.00 30.41 3.149 -7.059 -2.701 1.00 27.59 2.553 -6.2 16 -2.033 1.00 27.26 3.531 -8.199 -2.220 1.00 25.47 3.343 -8.497 -0.838 1.00 24.24 1.917 -9.019 -0.574 1.0026.56 1.653 -9.370 0.912 1.00 33.26 0.397-10.222 1.180 1.00 38.06 0.071 -11.150 0.423 1.00 40.20 -0.306 -9.9 19 2.289 1.00 38.60 4.357 -9.524 -0.384 1.00 21.45 4.500-10.565 -1.013 1.0022.59 5.102 -9.185 0.652 1.00 19.37 5.999-10.140 1.312 1.00 16.61 7.398 -9.539 1.501 1.00 13.50 8.171 -9.234 0.201 1.00 8.19 9.498 -8.580 0.509 1.00 3.80 8.404-10.519 -0.575 1.00 8.33 5.379 -10.490 2.673 1.00 15.88 4.921 -9.604 3.387 1.00 15.82 5.342-11.758 3.027 1.00 14.17 4.665-12.158 4.271 1.00 15.42 3.297 -12.694 3.909 1.00 16.35 2.309 -12.889 5.034 1.00 22.48 1.010-13.514 4.506 1.0029.57 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -241-

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1988 OEI GLN H 5 1989 NE2 GLN H 5 1992 C GLNH 5 1993 0 GLNH 5 1994 N GLUH 6 1996 CA GLU H 6 1997 CB GLU H 6 1998 CG GLU H 6 1999 CD GLU H 6 2000 OEI GLUH 6 2001 OE2GLUH 6 2002 C GLUH 6 2003 0 GLUH 6 2004 N SERH 7 2006 CA SER H 7 2007 CB SERH 7 2008 OG SER H 7 2010 C SERH 7 2011 0 SERH 7 2012 N GLYH 8 2014 CA GLY H 8 2015 C GLYH 8 2016 0 GLYH 8 2017 N GLYH 9 2019 CA GLYH 9 2020 C GLYH 9 2021 0 GLYH 9 2022 N GLYH 10 2024 CA GLYH 10 2025 C GLYH 10 2026 0 GLYH 10 2027 N LEUH 11 2029 CA LEU H 11 2030 CB LEUH 11 2031 CG LEUH I1 2032 CDILEUH 11 2033 CD2 LEU H 11 2034 C LEUH 11 2035 0 LEUH 11 2036 N VALH 12 2038 CA VALH 12 2039 CB VALH 12 2040 CGI VALH 12 2041 CG2 VALH 12 2042 C VALH 12 2043 0 VALH 12 2044 N GLNH 13 2046 CA GLN H 13 2047 CB GLN H 13 2048 CG GLN H 13 2049 CD GLN H 13 2050 OEI GLN H 13 2051 NE2GLNH 13 2054 C GLNH 13 2055 0 GLNH 13 2056 N PROH 14 0.404-14.362 5.167 1.00 35.66 0.575 -13.126 3.295 1.0031.58 5.480-13.205 5.006 1.00 13.97 5.597 -14.352 4.546 1.00 9.52 6.070-12.798 6.134 1.00 13.08 6.934 -13.696 6.901 1.00 9.47 7.857 -12.941 7.828 1.00 9.95 8.818 -12.002 7.134 1.00 9.95 8.227-10.652 6.796 1.00 5.17 9.024 -9.769 6.455 1.00 8.80 6.969-10.462 6.840 1.00 4.90 6.109-14.632 7.730 1.00 12.71 4.908-14.417 7.907 1.00 13.94 6.772-15.648 8.266 1.00 13.48 6.122 -16.647 5.433 -17.672 4.111 -17.308 7.122 -17.398 8.286 -17.424 6.633 -18.079 9.092 1.00 13.96 8.201 1.00 15.10 8.015 1.00 23.26 9.914 1.00 12.29 9.582 1.00 13.84 10.951 1.00 12.53 7.470-19.010 11.664 1.00 10.51 8.102-18.466 12.905 1.00 12.14 8.796-19.199 13.565 1.00 16.56 7.891 -17.195 13.244 1.00 10.59 8.519-16.693 14.462 1.00 14.05 7.917-17.287 15.762 1.00 16.57 6.760-17.790 15.781 1.00 17.72 8.670 -17.207 16.848 1.00 16.58 8.148-17.666 18.134 1.00 15.33 9.138-17.451 19.225 1.00 12.28 10.157-16.779 19.006 1.00 11.60 8.830-18.039 20.393 1.00 13.95 9.698-17.991 21.604 1.00 14.48 8.808 -18.086 22.841 1.00 14.29 9.212-17.437 24.171 1.00 13.64 8.438 -18.173 25.257 1.00 13.85 10.709 -17.464 24.470 1.00 4.07 10.568-19.230 21.585 1.00 14.46 10.064-20.286 21.346 1.00 15.77 11.839-19.104 21.907 1.00 18.00 12.751 -20.224 21.891 1.00 15.52 13.407 -20.306 20.461 1.00 18.43 14.920-20.197 20.558 1.00 13.84 13.000-21.593 19.746 1.00 16.77 13.825 -20.016 22.989 1.00 15.38 14.178-18.879 23.340 1.00 13.69 14.336-21.091 23.567 1.00 16.57 15.365 -20.936 15.307 -22.086 14.095 -22.089 14.433 -22.626 15.448 -23.315 13.591 -22.299 24.581 25.580 26.528 27.933 28.141 28.915 1.00 15.98 1.00 19.24 1.00 26.05 1.0028.25 1.0031.14 1.0033.04 1.00 14.00 1.00 15.42 1.00 12.23 16.710 -20.932 23.907 16.827 -21.336 22.748 17.718 -20.384 24.524 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -242-

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2057 CD PRO H- 14 2058 CA PROKH 14 2059 GB PRO H 14 2060 CG PRO H 14 2061 C PRO H 14 2062 0 PRO H 14 2063 N GLY H 15 2065 CA GLY H 15 2066 C GLY H 15 2067 0 GLY H 15 2068 N GLY H 16 2070 CA GLY H 16 2071 C GLY H 16 2072 0 GLY H 16 2073 N SER H 17 2075 CA SER H 17 2076 GB SER H 17 2077 OG SER H 17 2079 C SER H 17 2080 0 SER H 17 2081 N MET H 18 2083 CA MET H 18 2084 GB MET H 18 2085 CG MET H 18 2086 SD MET H 18 2087 CE MET H 18 2088 C MET H 18 2089 0 MET H 18 2090 N LYS H 19 2092 CA LYS H 19 2093 GB LYS H 19 2094 CG LYS H 19 2095 CD LYS H- 19 2096 CE LYS H 19 2097 NZ LYS H 19 2101 C LYS H 19 2102 0 LYS H 19 2103 N LEU H 20 2105 CA LEU H 20 2106 GB LEU H 20 2107 CG LEU H 20 2108 CD I LEU H 20 2109 CD2 LEU H 20 2110 C LEU H20 2111 0 LEU H 20 2112 N SER H 21 2114 CA SER H 21 2115 GB SER H 21 2116 OG SER H- 21 2118 C SER H 21 2119 0 SER H 21 2120 N CYS H 22 2122 CA CYS H 22 2123 GB CYS H 22 2124 SG CYS H 22 2125 C CYS H 22 17.678 -19.542 25.718 1.00 12.38 19.033 -20.406 23.936 1.00 12.75 19.910 -19.799 25.013 1.00 10.09 18.968 -18.787 25.569 1.00 13.06 19.388 -21.846 23.592 1.00 14.12 19.071 -22.767 24.361 1.00 16.21 20.018 -22.031 22.424 1.00 10.07 20.307 -23.367 21.913 1.00 7.80 19.223 -23.801 20.950 1.00 5.91 19.386 -24.766 20.199 1.00 6.43 18.140 -23.060 20.939 1.00 2.35 17.015 -23.419 20.123 1.00 6.43 17.257 -23.299 18.6 10 18.252 -22.759 18.149 16.260 -23.700 17.869 16.315 -23.739 16.416 16.721 -25.170 16.065 16.994 -25.349 14.706 1.00 6.38 1.00 6.92 1.00 12.18 1.00 11.41 1.00 15.73 1.00 22.31 14.907 -23.420 15.869 1.00 12.78 13.922 -23.8 16 16.484 1.00 16.32 14.790 -22.664 1 13.498 -22.456 12.582 -2 1.425 13.212 -20.131 12.014 -19.091 10.544 -20.141 13.678 -22.055 1 14.753 -21.621 1 12.630 -22.199 1 12.683 -21.822 12.600 -23.061 12.550 -22.781 13.032 -23.996 12.542 -24.031 11.259 -24.781 11.578 -20.848 1 10.407 -21.070 1 11.994 -19.744 11.101 -18.717 11.715 -17.332 12.256 -17.078 12.803 -15.654 11.165 -17.325 10.864 -18.860 11.728 -19.320 9.704 -18.485 7 9.321 -18.533 8.273 -19.604 8.807 -20.875 8.766 -17.205 5 8.163 -16.482 6 8.997 -16.872 4.769 1.00 8.79 14.119 1.00 10.28 14.819 1.00 13.63 15.329 1.00 16.88 16.241 1.00 27.06 16.251 1.00 3.15 2.669 1.00 9.07 2.252 1.00 10.49 1.905 1.00 10.93 10.529 1.00 11.83 9.621 1.00 14.90 8.090 1.00 17.52 7.304 1.00 20.23 5.860 1.00 19.51 5.747 1.00 22.58 0.212 1.00 13.18 0.524 1.00 12.84 9.604 1.00 12.76 9.170 1.00 9.79 9.456 1.00 11.85 10.883 1.00 9.81 10.965 1.00 4.16 .11.928 1.00 4.65 7.681 6.927 .288 5.9 15 5.7 17 6.0 12 .473 i.268 t. 199 1.00 9.78 1.00 8.56 1.00 9.36 1.00 13.01 1.00 14.00 1.00 19.15 1.00 13.78 1.00 18.18 1.00 16.70 8.489 -15.640 3.604 1.00 13.01 9.587 -14.560 3.529 1.00 11.58 9.150 -13.158 2.425 1.00 13.80 7.995 -15.917 2.193 1.00 11.47 SUBSTITUTE SHEET (RULE WO 99/10379 PCT/GB98/02542 -243-

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2126 2127 2129 2130 2131 2132 2133 2134 2135 2137 2138 2139 2140 2141 2143 2144 2145 2147 2148 2149 2151 2152 2153 2154 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2168 2169 2170 2172 2173 2174 2175 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2189 219( 219

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CYS H 22 4 VAL H 23 'A VAL H 23 'B VAL H 23 SGI VAL H 23 'G2 VAL H 23 VAL H 23 VAL H 23 4 ALA H 24 'A ALA H 24 'B ALA H 24 ALA H 24 ALA H 24 q SER H 25 "A SER H 25 :B SER H 25 )G SER H 25 SER H 25 D SER H 25 8.718-16.418 1.374 1.00 13.22 6.773 -15.589 1.935 1.00 14.16 6.195 -15.809 0.631 1.0016.31 4.871 -16.609 0.733 1.00 17.85 5.162-17.918 1.444 1.0021.18 3.811 -15.831 1.493 1.00 19.36 5.927-14.486 -0.033 1.00 16.44 5.313 -13.580 6.385 -14.400 6.247 -13.181 7.568 -12.903 5.143 -13.311 4.881 -14.410 4.488 -12.222 3.474 -12.266 2.151 -12.592 1.844 -11.601 0.565 -1.280 -2.088 -2.774 -3.132 -3.666 -3.434 -4.447 -3.804 -2.853 1.00 12.06 1.00 19.48 1.00 19.91 1.00 18.96 1.00 21.31 1.00 24.23 1.00 19.69 1.00 20.48 1.00 19.79 1.00 22.03 N GLY H 26 CA GLY H 26 C GLY H 26 O GLY H 26 N PHE H 27 CA PHE H 27 CB PHE H 27 CG PHE H 27 CDI PHE H 27 CD2 PHE H 27 CEI PHE H 27 CE2 PHE H 27 CZ PHE H 27 C PHE H 27 O PHE H 27 N THR H 28 CA THR H 28 CB THRH 28 OGI THR H 28 CG2 THR H 28 C THR H 28 O THR H 28 N PHE H 29 CA PHE H 29 CB PHE H 29 CG PHE H 29 CDI PHE H 29 CD2 PHE H 29 CEI PHE H 29 CE2 PHE H 29 CZ PHE H 29 C PHE H 29 60 PHE H 29 7 N SER H 30 9 CA SERH 30 0 CB SER H 30 1 OG SER H 30 3.379-10.931 -5.124 1.00 20.75 3.861 -9.929 -4.589 1.00 20.32 2.745 -10.910 -6.292 1.00 22.48 2.518 -9.640 -6.979 1.00 24.12 3.711 -9.128 -7.798 1.00 25.02 3.707 -7.958 -8.219 1.00 22.99 4.720 -10.012 -8.005 1.0024.04 5.913 -9.716 -8.804 1.00 22.13 6.808 -8.655 -8.126 1.00 23.23 7.717 -9.176 -7.022 1.00 20.65 9.094 -9.334 -7.249 1.00 19.81 7.213 -9.450 -5.750 1.00 19.64 9.940 -9.755 -6.225 1.00 18.67 8.061 -9.857 -4.730 1.00 16.42 9.416-10.009 -4.964 1.00 16.29 6.718 -11.005 -9.015 1.00 22.10 6.502 -12.018 -8.322 1.0025.47 7.682 -10.944 -9.919 1.00 17.46 8.478-12.086-10.239 1.00 16.95 9.042 -11.939 -11.629 1.00 18.84 7.933 -11.701 -12.512 1.00 19.87 9.787-13.199-12.039 1.00 17.78 9.588-12.303 -9.265 1.00 16.32 10.746-11.886 -9.500 1.00 13.29 9.237 -13.018 -8.187 1.00 17.39 10.182-13.315 -7.097 1.00 12.65 9.507-14.279 -6.097 1.00 14.38 10.397 -14.838 -5.015 1.00 13.29 10.551 -14.153 -3.797 1.00 17.17 11.053 -16.054 -5.178 1.00 11.79 11.356 -14.678 -2.770 1.00 16.24 11.856-16.589 -4.162 1.00 8.50 12.012-15.903 -2.965 1.00 14.16 11.474 -13.895 -7.603 1.00 11.31 12.546-13.535 -7.107 1.00 11.15 11.384-14.789 -8.634 1.00 10.88 12.574-15.473 -9.198 1.00 10.24 12.135-16.414-10.355 1.00 10.59 10.724 -16.474 -10.445 1.00 20.09 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -244-

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2193 2194 2195 2197 2198 2199 2200 2201 2204 2205 2206 2208 2209 2210 2211 2212 2213 2214 2215 2216 2218 2219 2220 2222 2223 2224 2225 2226 2227 2228 2229 2231 2232 2233 2234 2235 2236 2238 2239 2240 2241 2242 2243 2244 2245 224', 2241 2245 225( 225 225' 225: 225i 225: 225 226 C SERH 30 O SER H 30 N ASNH 31 CA ASN H 31 CB ASN H 31 CG ASN H 31 OD1 ASN H 31 ND2 ASN H 31 C ASN H 31 O ASNH 31 N TYR H 32 CA TYR H 32 GB TYR H 32 CG TYR H 32 CDI TYR H 32 GEI TYR H 32 CD2 TYR H 32 CE2 TYR H 32 CZ TYR H 32 OH TYR H 32 C TYR H32 0 TYR H 32 N TRP H 33 CA TRP H 33 CB TRP H 3 3 CG TRP H 33 CD2 TRP H 33 GE2 TRP H 33 CE3 TRP H 33 CD1 TRP H 33 NEI TRPH 33 CZ2 TRP H 33 CZ3 TRP H 33 CH2 TRP H 33 C TRP H33 0 TRP H 33 N MET H34 CA MET H 34 CB MET H 34 C G MET H 34 SD MET H 34 GE MET H 34 C MET!-H 34 I0 MET H 34 ~N ASN H35 C A ASN H 35 C B ASN H 35 SCG ASN H 35 0 ODI ASN H 3~ 1 ND2 ASN H 3~ 4 C ASN H 35 5 0 ASN H35 6 N TRP H36 8 CA TRP H 36 9 GB TRPH 36 0 CG TRP H 36 13.663 -14.525 -9.728 1.00 8.21 14.843 -14.915 -9.841 1.00 6.56 13.251 -13.294 -10.108 1.00 10.86 14.160 -12.317 -10.733 1.00 10.45 13.370-11.295-11.558 1.00 13.88 12.872 -11.818 -12.880 1.00 17.90 13.232 -12.928 -13.299 1.00 17.77 12.031 -1 1.021 -13.543 1.00 20.48 15.023 -11.519 -9.758 1.00 11.11 15.975 -10.849 -10.191 1.00 11.57 14.675 -11.517 -8.473 1.00 10.42 15.442 -10.727 -7.5 15 1.00 7.72 14.550 -9.654 -6.923 1.00 10.35 13.981 -8.740 -7.960 1.00 10.12 12.704 -8.983 -8.463 1.00 11.35 12.183 -8.238 -9.523 1.00 13.96 14.743 -7.719 -8.533 1.00 10.05 14.228 -6.955 -9.615 1.00 10.42 12.946 -7.222 -10.097 1.00 13.65 12.371 -6.438 -11.090 1.00 13.93 16.056 -11.540 -6.386 1.00 8.75 15.547 -12.606 -6.002 1.00 8.92 17.167 -11.022 -5.866 1.00 7.78 17.751 -11.575 -4.714 1.00 6.34 19.104 -10.957 -4.367 1.00 3.32 20.137 -10.913 -5.428 1.00 5.31 21.483 -10.438 -5.249 1.00 2.32 22.117 -10.500 -6.509 1.00 3.83 22.201 -9.970 -4.150 1.00 5.74 19.998 -11.243 -6.757 1.00 2.00 21.186 -10.988 -7.387 1.00 3.99 23.426 -10.096 -6.703 1.00 5.36 23.503 -9.568 -4.337 1.00 8.48 24.101 -9.632 -5.608 1.00 7.99 16.821 -11.212 -3.557 1.00 8.26 16.053 -10.225 -3.649 1.00 6.24 16.911 -11.997 -2.481 1.00 7.22 5 16.133 -11.752 15.113 -12.860 13.919 -12.749 12.885 -11.275 11.928 -11.767 17.094 -11.681 18.197 -12.256 16.736 -10.899 17.586 -10.755 18.198 -9.339 18.906 -8.804 20.148 -8.700 18.121 -8.476 16.737 -10.94 1 15.499 -10.824 17.404 -11.282 16.755 -11.238 16.888 -12.554 15.911 -13.575 -1.269 1.00 8.81 -1.108 1.00 7.01 -2.056 1.00 10.07 -1.844 1.00 17.49 -0.412 1.00 17.44 0.057 1.00 7.51 .107 1.00 10.32 0.981 1.00 6.44 2.175 1.00 4.54 2.317 1.00 5.78 1.078 1.00 3.57 1.016 1.00 2.44 0.102 1.00 2.00 3.433 1.00 4.23 3.380 1.00 2.00 4.532 1.00 4.82 5.831 1.00 6.51 6.607 1.00 4.15 6.121 1.00 6.17 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542

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2261 2262 2263 1264 2265 2267 2268 2269 2270 2271 2272 2274 2275 2276 2277 2278 2279 2280 2282 2283 2284 2285 2286 2288 2289 2292 2295 2296 2297 2299 2300 2301 2302 2303 2304 2307 2308 2309 2311 2312 2313 2315 2316 2317 231 231 232( 232 232: 232: 232.

232 232 232 232 233 CD2TRPH 36 CE2 TRP H 36 CE3 TRP H 36 CDI TRPH 36 NEI TRP H 36 CZ2 TRP H 36 CZ3 TRP H 36 CH2 TRP H 36 C TRP H 36 O TRP H 36 N VAL H 37 CA VAL H 37 CB VAL H 37 CGI VAL H 37 CG2 VAL H 37 C VAL H 37 O VAL H 37 N ARG H 38 CA ARG H 38 CB ARG H 38 CG ARG H 38 CD ARG H 38 NE ARG H 38 CZ ARG H 38 NH1 ARG H 38 NH2 ARG H 38 C ARG H 38 O ARG H 38 N GLN H 39 CA GLN H 39 CB GLN H 39 CG GLN H 39 CD GLN H 39 OEI GLN H 39 NE2 GLN H 39 C GLN H 39 O GLN H 39 N SERH 40 CA SERH 40 CB SERH 40 SOG SER H 40 C SERH 40 O SERH 40 N PRO H 41 8 CD PRO H 41 9 CA PRO H 41 0 CB PRO H 41 1 CG PRO H 41 2 C PROH 41 3 0 PROH 41 4 N ALA H 42 6 CA ALA H 42 7 CB ALA H 42 8 C ALA H 42 9 O ALA H 42 0 N LYS H 43 14.527-13.755 13.987-14.743 13.668-13.180 16.138-14.443 14.995-15.119 12.650-15.189 12.315-13.631 -245- 6.513 5.672 1 7.489 I 5.102 4.847 5.749 1 7.564 1 5.59 7.68 3.55 7.43 11.31 7.42 2.61 11.829-14.613 6.706 1.00 5.75 17.391 -10.102 6.614 1.00 3.69 18.617 -9.907 6.585 1.00 3.88 16.565 -9.310 7.251 1.00 8.04 17.074 -8.206 8.049 1.00 4.88 16.856 -6.854 7.314 1.00 7.93 17.122 -5.671 8.277 1.00 5.70 17.779 -6.772 6.078 1.00 4.88 16.275 -8.201 9.356 1.00 7.96 15.062 -8.279 9.294 1.00 10.89 16.929 -8.083 10.499 1.00 4.79 16.186 -8.134 11.784 1.00 6.19 16.715 -9.294 12.691 1.00 2.00 18.083 -9.070 13.402 1.00 5.85 18.660-10.356 14.068 1.00 7.03 20.113-10.243 14.278 1.00 5.02 20.880-11.237 14.678 1.00 7.94 22.163-11.027 14.921 1.00 8.02 20.378-12.448 14.813 1.00 10.78 16.224 -6.783 12.565 1.00 9.00 17.177 -5.984 15.193 -6.535 15.146 13.914 13.835 12.562 11.554 12.580 -5.313 -4.517 -3.170 -2.454 -3.054 -1.161 12.474 13.334 14.106 13.693 14.378 14.079 4 13.63 1 14.31 1.00 7.20 1.00 10.07 1.00 13.88 1.00 12.70 1.00 13.88 1.00 10.90 7 1.00 14.02 1 1.00 19.33 15.092 -5.640 14.153 -6.324 16.117 -5.159 1 16.190 -5.352 17.407 -6.212 18.567 -5.412 16.346 -3.997 1 16.983 -3.109 15.798 -3.822 15.063 -4.844 15.899 -2.545 15.210 -2.883 15.328 -4.371 15.634 1.00 17.21 16.086 1.00 11.06 6.390 1.00 20.54 17.844 1.00 25.32 18.210 1.00 24.24 18.281 1.00 26.93 8.533 1.0026.35 17.969 1.00 27.60 19.781 1.0029.80 20.562 0.50 26.67 20.545 1.00 29.86 21.864 0.50 28.55 21.952 0.50 27.83 17.369 -2.074 20.736 1.00 33.07 17.754 -0.924 20.401 1.00 33.27 18.194 -2.987 21.203 1.00 34.06 19.603 -2.677 21.457 1.00 37.51 20.208 -3.808 22.297 1.00 37.30 20.447 -2.482 20.170 1.00 37.45 21.605 -2.039 20.248 1.00 38.47 19.881 -2.791 18.996 1.0036.93 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -246-

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2332 2333 2334 2335 2336 2337 2341 2342 2343 2345 2346 2347 2348 2350 2351 2352 2353 2354 2355 2356 2357 2359 2360 2361 2362 2363 2364 2365 2366 2367 2369 2370 2371 2372 2373 2374 2375 2376 2378 2379 2380 2381 2382 2383 2385 2386 2387 2388 2389 2390 2391 2393 2394 2395 239( 239', LYS H 43 LYS H 43 iLYS H 43 LYS H 43 LYS H 43 LYS H 43 LYS H 43 LYS H 43 GLY H 44 LGLY H 44 GLY H 44 GLY H 44 LEU H 45 20.694 -2.8 12 21.032 -4.263 2 1.896 -4.979 22.480 -6.299 21.507 -7.487 22.138 -8.774 20.086 -2.153 1 20.742 -2.1151 18.883 -1.625 18.269 -1.095 18.252 -2.177 18.077 -3.382 18.484 -1.780 18.439 -2.758 17.995 -2.110 16.506 -1.789 17.802 17.457 18.496 17 .956 18.083 17.647 6.574 5.545 16.653 LO0035.11 1.00 36.81 1.00 40.66 1.00 40.17 1.00 38.65 1.00 34.06 1.00 32.32 1.00 32.74 1.00 28.07 15.433 1.00 26.41 14.336 1.00 22.61 14.667 1.00 21.36 13.056 1.00 18.78 11.923 1.00 14.74 10.590 1.00 10.90 10.431 1.00 7.35 CA LEU H 45 CB LEU H 45 CG LEU H 45 CDI LEU H 45 CD2 LEU H 45 C LEU H45 O LEU H45 N GLU H46 CA GLU H 46 GB GLU H 46 CG GLU H 46 CD GLU H 46 OEI GLU H 46 0E2 GLU H 46 C GLU H46 O GLU H 46 N TRP H47 CA TRP H 47 GB TRP H 47 CG TRP H 47 CD2 TRP H 47 CE2 TRP H 47 CE3 TRP H 47 CD1 TRP H 47 NEI TRP H 47 CZ2 TRP H 47 CZ3 TRP H 47 CH2 TRP H 47 C TRP H47 0 TRP H47 N VAL H48 CA VAL H 48 GB VAL H 48 CG IVAL H 48 CG2 VAL H 48 C VAL H48 10 VAL H48 N ALA H49 ICA ALA H 49 C B ALA H 49 CG ALA H49 0O ALA H49 TN GLUH 50 16.262 -1.110 9.115 15.627 -3.031 10.53: 19,759 -3.470 11.715 20.859 -2.873 11.722 19.676 -4.774 11.523 20.884 -5.550 21.280 -6.310 22.748 -6.634 23.081 -7.707 22.443 -7.73 5 23.996 -8.5 14 11 .294 12.572 12.653 13.669 14.75: 13.38 1.00 8.68 11.00 4.89 1.00 13.85 1.00 11.97 1.00 13.05 I1.00 10.92 1.00 12.86 1.0021.14 11.00 24.52 3 1.0028.63 7 1.00 25.36 20.644 -6.543 19.712 -7.358 2 1.457 -6.432 21.327 22.045 22.145 23 .284 22.977 24.546 21.183 2 1.707 23.875 25.423 -7.309 -6.698 -7.629 -8.45' -9.168 -8.669i -7.86: -8.79: -10.06 -9.56( 10.145 1.00 9.90 10.197 1.00 6.95 9.110 1.00 7.54 7.968 1.00 7.90 6.731 1.00 10.76 5.553 1.00 5.45 5.230 1.00 3.79 14.069 1.00 2.00 15.829 1.00 3.96 34.590 1.00 4.22 3 3.707 1.00 5.25 0 3.490 1.00 2.56 5.251 1.00 2.00 25.079 -10.232 4.094 1.00 2.00 21.908" -8.649 8.352 1.00 2.55 22.958 -8.730 8.976 1.00 5.06 21.209 -9.667 7.995 1.00 6.21 21.538 -10.996 8.431 1.00 7.94 20.256 -11.544 9.165 1.00 7.86 20.190 -13.054 9.168 1.00 10.48 20.234 -10.992 10.603 1.00 4.08 22.041 -11.928 23.086 -12.617 21.334 -11.913 21.687 -12.816 21.194 -14.210 21.046 -12.385 20.003 -11.745 21.696 -12.784 7.262 7.396 6.123 5.031 5.349 3.728 3.740 2.609 1.00 8.81 1.00 5.89 1.00 6.18 1.00 4.66 1.00 2.00 1.00 5.58 1.00 7.99 1.00 7.04 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCTIGB98/02542 -247-

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2399 2400 2401 2402 2403 2404 2405 2406 2407 2409 2410 2411 2412 2413 2414 2415 2416 2418 2419 2420 2421 2422 2424 2425 2428 2431 2432 2433 2435 2436 2437 2438 2439 2440 2441 2442 2444 2445 2446 2447 2448 2449 2453 2454 2455 2457 2458 2459 2461 2462 2463 2465 246( 2462, 246~ 246' GA GLU H 50 GB3 GLU H 50 CG GLU H 50 CD GLU H 50 OEI GLU H 50 OE2 GLU H 50 C GLU H 50 O GLUE-ISO N ILE H 51 CA ILEKH 51 GB3 ILE H 51 CG2 ILE H 51 CGGIILE H 51 CD ILE H 51 C ILE H 51 O ILE H 51 N ARG H52 CA ARG H 52 GB3 ARG H 52 CG ARG H 52 CD ARG H 52 NE ARG H 52 CZ ARG H 52 NH IARG H 52 NH-2 ARG H 52 C ARG H 52 O ARG H 52 N LEUH 52A CA LEU H 52, GB3 LEU H 52~ CG LEU H 52i CDI LEU H 52 CD2 LEU H 52 C LEU H 52A O LEU H 52A N LYS H 52B CA LYS H 521 GB3 LYS H 521 GG LYS H 52] CD LYS H- 521 GE LYS H 521 NZ LYS H 521 C LYS H52B O LYS H 52B N SERKH 52C GA SER H 52' GB3 SER H 524 4OG SER H 52 C SER H 52C O SERMH 52C N ASN H 53 GA ASN H 53 GB ASN H 53 1CG ASN H 53 ODI ASN H 5 ND2 ASN H 5 21.163 -12.558 21.979 -11.510 23.410 -11.908 24.060 -11.041 24.890 -11.555 23.733 -9.831 1.264 1.00 8.25 0.501 1.00 9.60 0.258 1.00 7.83 -0.762 1.00 13.01 -1.523 1.00 9.53 -0.810 1.00 13.19 21.271 -13.869 0.479 1.00 6.87 22.100 -14.697 0.811 1.00 5.50 20.411 -14.037 -0.511 1.00 7.46 20.504 -15.187 -1.426 1.00 6.66 19.517 -16.301 -1.071 1.00 3.45 18.070 -15.818 -1.217 1.00 9.97 19.780 -17.539 -1.911 1.00 2.00 18.845 -18.675 -1.563 1.00 2.00 20.238 -14.704 -2.859 1.00 5.59 19.284 -13.985 -3.134 1.00 5.07 21.096 -15.107 -3.756 1.00 6.35 20.994 -14.629 -5.120 1.00 8.96 22.408 -14.461 -5.694 1.00 5.72 23.474 -14.3 44 -4.589 1.00 12.48 24.048 -12.970 -4.373 1.00 13.83 25.246 -12.780 -5.134 1.00 12.25 26.246 -11.933 -4.828 1.00 12.96 27.255 -11.857 -5.635 1.00 11.49 26.249 -11.156 -3.759 1.00 14.67 20.089 -15.503 -5.973 1.00 10.32 19.257 -16.224 -5.438 1.00 8.96 20.244 -15.437 -7.320 1.00 9.13 k 19.300 -16.095 -8.199 1.00 9.35 k 19.204 -15.297 -9.499 1.00 8.23 k 19.031 -13.765 -9.341 1.00 4.43 A 19.048 -13.106 -10.712 1.00 9.87 A 17.727 -13.445 -8.645 1.00 4.72 19.657 -17.540 -8.504 1.00 6.27 20.750 -18.001 -8.220 1.00 6.95 18.723 -18.250 -9.074 1.00 7.45 3 19.023 -19.580 -9.558 1.00 11.04 3 17.873 -20.081 -10.384 1.00 13.40 B 18.078 -21.510 -10.825 1.00 18.86 B 16.930 -21.989 -11.679 1.0021.41 3 17.323 -23.278 -12.418 1.00 27.85 B 16.318 -23.616 -13.459 1.0034.07 20.289 -19.578 -10.406 1.00 11.82 21.181 -20.376 -10.179 1.00 10.65 20.369 -18.635 -11.381 1.00 10.14 C 21.525 -18.526 -12.237 1.00 8.75 C 21.282 -17.520 -13.358 1.00 11.63 C 20.885 -16.286 -12.846 1.00 15.43 22.786 -18.177 -11.507 1.00 11.06 23.852 -18.244 -12.093 1.00 9.23 22.687 -17.797 -10.207 1.00 10.74 23.890 -17.552 -9.399 1.00 11.27 23.664 -16.369 -8.474 1.00 10.94 23.347 -15.139 -9.257 1.00 8.42 3 22.269 -14.573 -9.150 1.00 12.13 3 24.281 -14.733 -10.056 1.00 10.17 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -248-

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2472 2473 2474 2476 2477 2478 2479 2480 2483 2484 2485 2487 2488 2489 2490 2491 2492 2493 2494 2495 2497 2498 2499 2501 2502 2503 2504 2505 2507 2508 2509 2511 2512 2513 2514 2516 2517 2518 2519 2520 2522 2523 2525 2526 2527? 2529 2530 2531 2532 2533 2534 2535 253( 2537 253~ 254( C ASN H53 ASN H53 N ASNHS54 CA ASN H 54 CB ASN H 54 CG ASN H 54 OD I ASN H 54 ND2 ASN H 54 C ASNH 54 0 ASN H 54 N TYR H 55 CA TYRI-H 55 CB TYRKH 55 CG TYR H 55 CDI TYR H 55 GEl TYR H 55 CD2 TYR H 55 CE2 TYR H 55 CZ TYRKH 55 OH TYR H 55 C TYR H 55 O TYR H 55 N ALAH 56 CA ALA H 56 CB ALA H 56 C ALAH 56 0 ALAH 56 N THR H 57 CA THR H 57 GB TER H 57 OGI THRH 57 CG2 THR H 57 C THR H 57 0 THR H 57 N HISH 58 CA HIS H 58 GB HIS H 58 CG HIS H 58 CD2 HIS H 58 NDI HIS H 58 GEl HIS H 58 NE2 HIS H 58 C HISH 58 0 H-IS H 58 N TYRH 59 CA TYR H 59 C B TYR H 59 CG TYR H 59 CD1 TYR H 59 I l TYR H 59 ICD2 TYR H 59 CE2 TYR H 59 CZ TYRKH 59 1OH TYR H- 59 C TYRMH 59 0O TYRH 59 24.200 -18.799 -8.559 1.00 10.33 25.123 -18.802 -7.711 1.00 9.92 23.433 -19.867 -8.841 1.00 10.20 23.553 -21.171 -8.120 1.00 10.20 25.018 -21.608 -7.987 1.00 6.42 25.728 -2 1.672 -9.344 1.00 8.73 25.259 -22.3 10 -10.276 1.00 8.04 26.831 -20.992 -9.465 1.00 4.73 22.954 -2 1.063 -6.718 1.00 11.89 23.310 -21.844 -5.837 1.00 12.26 22.027 -20.102 -6.536 1.00 9.38 21.467 -19.805 -5.191 1.00 8.46 20.675 -20.998 -4.712 1.00 2.42 19.506 -21.296 -5.592 1.00 8.11 19.493 -22.436 -6.421 1.00 9.49 18.379 -22.709 -7.234 1.00 12.87 18.408 -20.468 -5.600 1.00 4.03 17.3 13 -20.726 -6.393 1.00 11.68 17.296 -21.852 -7.220 1.00 15.91 16.178 -22.098 -8.056 1.00 20.99 22.591 -19.439 -4.184 1.00 8.90 22.558 -19.848 -3.000 1.00 12.11 23.578 -18.631 -4.656 1.00 5.77 24.694 -18.199 -3.833 1.00 7.06 25.723 -17.516 -4.733 1.00 11.84 24.2 14 -17.266 -2.667 1.00 7.10 23.170 -16.606 -2.757 1.00 5.63 24.963 -17.246 -1.571 1.00 7.85 24.500 -16.552 -0.372 1.00 6.03 23.968 -17.571 0.680 1.00 4.33 25.027 -18.488 1.036 1.00 3.89 22.767 -18.362 0.166 1.00 3.87 25.616 -15.821 0.286 1.00 4.64 26.803 -16.086 0.030 1.00 7.15 25.259 -14.857 1.133 1.00 5.83 26.265 -14.223 2.005 1.00 2.00 26.868 -12.919 1.470 1.00 4.50 27.547 -13.109 0.164 1.00 4.63 28.832 -13.271 -0.177 1.00 7.27 26.850 -13.173 -0.991 1.00 5.48 27.613 -13.361 -2.013 1.00 8.70 28.822 -13.418 -1.542 1.00 9.97 25.588 -13.987 3.334 1.00 2.00 24.363 -13.904 3.369 1.00 2.00 26.384 -13.953 4.377 1.00 3.87 25.875 -13.909 5.761 1.00 6.14 26.152 -15.253 6.442 1.00 4.65 25.309 -16.336 5.884 1.00 2.93 25.788 -17.155 4.883 1.00 7.71 24.973 -18.093 4.290 1.00 5.29 23.985 -16.488 6.289 1.00 4.20 23.184 -17.418 5.699 1.00 5.04 23.705 -18.212 4.689 1.00 5.90 22.942 -19.140 4.124 1.00 9.69 26.600 -12.897 6.559 1.00 6.82 27.771 -12.697 6.337 1.00 7.72 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/G B98/02542 -249- ATOM 2541 N ALA H 60 ATOM 2543 CA ALA H 60 ATOM 2544 GB ALA H 60 ATOM 2545 C ALA H 60 ATOM 2546 0 ALA H 60 ATOM 2547 N ALA H 61 ATOM 2549 CA ALA H 61 ATOM 2550 GB ALA H 61 ATOM 2551 C ALA H 61 ATOM 2552 0 ALA H 61 ATOM 2553 N SER H 62 ATOM 2555 CA SER H 62 ATOM 2556 GB SER H 62 ATOM 2557 OG SER H 62 ATOM 2559 C SER H 62 ATOM 2560 0 SER H 62 ATOM 2561 N VAL H 63 ATOM 2563 CA VAL H 63 ATOM 2564 GB VAL H 63 ATOM 2565 CGlI VAL H 63 ATOM 2566 CG2 VAL H 63 ATOM 2567 C VAL H 63 ATOM 2568 0 VAL H 63 25.925 -12.282 26.639 -11.382 25.661 -10.580 27.486 -12.224 27.095 -13.356 28.630 -11.687 29.557 -12.439 30.778 -11.575 7.515 1.00 8.95 8.424 1.00 6.79 9.276 1.00 8.53 9.322 1.00 10.22 9.685 1.00 11.26 9.73 1 1.00 13.53 10.577 1.00 14.91 10.917 1.00 14.40 28.899 -12.973 11.866 29.251 -14.049 12.335 27.923 -12.257 12.408 27.304 -12.651 13.691 26.493 -11.485 14.211 25.625 -10.986 13.206 26.378 -13.857 13.557 25.799 -14.355 14.542 26.235 -14.324 12.3 50 25.239 -15.311 12.066 24.130 -14.543 11.334 23.637 -15.237 10.09 23.017 -14.228 12.33 25.838 -16.474 11.274 25.290 -17.566 11.214 27.015 -16.239 10.768 ATOM

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2569 2571 2572 2573 2574 2575 2576 2580 2581 2582 2584 2585 2586 2587 2589 2590 2591 2592 2593 2595 2596 2599 2602 2603 2604 2606 2607 2608 2609 2610 2611 2612 2613 LYS H 64 LYS H 64 LYS H 64 LYS H 64 LYS H 64 LYS H 64 LYS H 64 LYS H 64 LYS H 64 GLY H 65 GLY H 65 GLY H 65 GLY H 65 ARG H 66 ARG H 66 1 ARG H 66 i ARG H- 66 ARG H 66 "ARG H 66 ARG H 66 27.688 -17.213 29.059 -16.666 29.150 -16.132 30.593 -15.735 30.751 -15.203 32.163 -14.833 27.858 -18.496 28.225 -18.458 27.565 -19.618 9.966 9.545 8.136 7.835 6.425 6.129 10.756 11.926 10.110 1.00 17.24 1.00 21.67 1.00 18.88 1.0020.00 1.00 16.39 1.00 18.61 1.00 21.12 1.00 19.05 1.00 18.08 1.00 17.68 1.00 18.65 2 1.00 16.99 3 1.00 12.88 1.00 15.76 1.00 14.97 1.00 18.14 1.00 20.28 1.00 22.43 1.00 20.56 1.00 23. 16 0.01 21.98 0.01 23.60 1.00 18.78 1.00 20.26 1.00 17.68 1 1.00 16.07 1.00 14.30 1.00 14.97 1.00 14.24 4 1.00 10.28 2 1.00 7.89 3 1.00 7.93 3 1.00 14.73 2 1.00 17.33 0 1.00 17.22 10 1.00 18.44 30 1.00 15.39 1.00 9.54 1.00 11.68 1.00 9.08 5 1.00 8.27 Z1.00 14.66 5 1.00 11.27 2 1.00 16.10 0 1.00 12.21 9 1.00 15.15 3 1.00 16.05 81.00 14.19 27.700 -20.9 19 10.76' 26.476 -21.353 11.581 26.364 -22-.517 11.931 NH I ARG H 66 NH2 ARG H 66 C ARG H66 0 ARG H66 N PHE H67 CA PHE H 67 GB PHE H 67 CG PHE H 67 CDI PHE H 67 CD2 PHE H 67 GEI PHE H 67 CE2 PHE H 67 CZ PHEMH 67 25.553 -20.432 1 24.336 -20.780 24.261 -19.924 25.503 -20.000 25.673 -18.695 24.525 -18.448 23.913 -17.292 22.879 -17.258 24.3 19 -16.184 23.090 -20.589 1 22.071 -21.275 1 23.106 -19.623 1' 21.905 -19.393 21.485 -17.896 20.955 -17.333 20.951 -18.096 20.441 -16.043 20.452 -17.567 19.943 -15.515 19.952 -16.276 1.876 12.62 13.86: 14.71: 15.48, 16.27: 1'6.394 17.1 15.8( 1.803 2.0 11 0.884 10.05~ 10.06 11.36: 12.55 11.41 13.73 12.60 13.751 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -250-

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~614 ~615 ~616 ~618 1619 1620 622 Z623 624 2625 2627 2628 2629 2630 2631 2632 2633 2634 2636 2637 2638 2640 2641 2642 2644 2645 2646 2647 2648 2650 C PHE H67 PHE H67 N THR H68 CA THR H 68 GB THR H 68 OG ITHR H 68 CG2 THR H 68 C THR H 68 O THR H68 N ILE H69 CA ILE H 69 GB ILE H 69 CG2 ILE H 69 CG I ILE H 69 CD ILE H 69 C ILE H69 O ILE H 69 N SER H 70 CA SER H 70 C1B SER H 70 OG SER H 70 C SERH 70 O SER H70 N ARG H71 22.151 -19.809 8.590 1.00 8.04 23.308 -19.737 8.107 1.00 7.14 2 1.069 -20.222 7.902 1.00 5.55 21.135 -20.635 6.488 1.00 6.31 21.138 -22.179 6.392 1.00 10.66 22.268 -22.681 7.120 1.00 8.86 21.158 -22.667 4.935 1.00 10.19 19.909 -20.118 5.735 1.00 6.07 18.761 -20.448 6.076 1.00 9.45 20.134 -19.267 4.742 1.00 4.87 19.048 -18.766 3.956 1.00 2.00 19.312 -17.255 3.525 1.00 6.99 20.551 -17.113 2.660 1.00 7.03 18.099 -16.665 2.797 1.00 2.00 18.333 -15.229 2.387 1.00 2.00 18.896 -19.677 2.718 1.00 2.51 19.874 -20.22 1 2.257 1.00 2.38 17.690 -19.872 2.253 1.00 2.57 17.478 -20.679 1.081 1.00 6.14 17.375 -22.176 1.473 1.00 9.52 16.243 -22.479 2.291 1.00 10.39 16.224 -20.206 0.384 1.00 6.48 15.483 -19.433 0.956 1.00 7.77 15.977 -20.635 -0.859 1.00 7.82 14.771 -20.200 -1.545 1.00 8.16 15.013 -18.926 -2.433 1.00 10.92 16.003 -19.089 -3.610 1.00 8.76 16.351 -17.736 -4.291 1.00 4.61 15.173 -17.037 -4.839 1.00 7.09 15.201 -15.734 -5.185 1.00 7.29 1 14.129 -15.130 -5.657 1.00 8.76 1 16.294 -15.048 -5.020 1.00 3.13 CA ARG H 71 GB ARG H 71 CG ARG H 71 CD ARG H 71 NE ARG H 71 CZ ARG H 71 NHI ARGH 7 NH2 ARG H 7 2651 2654 2657 2658 2659 2661 2662 2663 2664 2665 2666 2667 2668 2670 2671 2672 2673 2674 2675 2676 2677 2679 2680 2681 2683 268' C ARG H71 0 ARG H71 N ASP H72 CA ASP H 72 GB ASP H 72 CG ASP H 72 ODI ASP H 72 0D2 ASP H 72 C ASP H72 0 ASP H 72 N ASP H73 CA ASP H 73 GB3 ASP H 73 CG ASP H 73 ODI ASP H 73 OD2 ASP H 73 C ASP H73 0 ASP H 73 ~N SER H74 ICA. SER H 74 C1B SERKH 74 OG SER H 74 IC SER H 74 10 SER H74 14.170 -21.289 -2.385 14.832 -22.200 -2.8 14 12.920 -21.167 -2.619 12.275 -22.064 -3.477 11.461 -23.048 -2.660 10.873 -24.134 -3.531 1.00 9.04 1.00 11.10 1.00 8.40 1.00 13.86 1.00 18.00 1.00 22.29 9.993 -23.8 18 -4.333 1.00 18.82 11.286-25.303 -3.392 1.00 29.08 11.402 -21.244 -4.397 1.00 12.87 10.324 -20.782 -4.036 1.00 11.56 11.894 -21.045 -5.587 1.00 14.62 11. 183 -20.241 -6.506 1.00 12.47 12.023 -19.903 -7.750 1.00 14.32 13.316 -19.152 -7.394 1.00 12.44 13.315 -18.402 -6.404 1.00 13.98 14.333 -19.334 -8.080 1.00 14.38 9.918 -20.906 -6.865 1.00 15.39 8.966 -20.160 -7.111 1.00 17.19 9.842 -22.307 -6.828 1.00 16.30 8.521 -22.992 -7.159 1.00 17.45 8.491 -24.605 -7.038 1.00 15.19 9.303 -25.285 -6.039 1.00 2.00 7.416 -22.405 -6.303 1.00 19.15 6.283 -22.217 -6.761 1.00 16.07 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 1- ATOM 2685 N LYS H 75 ATOM 2687 CA LYS H 75 ATOM 2688 GB LYS H 75 ATOM 2689 CG LYS H 75 ATOM 2690 CD LYS H 75 ATOM 2691 CE LYS H 75 ATOM 2692 NZ LYS H 75 ATOM 2696 C LYS H 75 ATOM 2697 0 LYS H 75 ATOM 2698 N SER H 76 ATOM 2700 CA SER H 76 ATOM 2701 GB SER H 76 ATOM 2702 OG SER H 76 ATOM 2704 C SER H 76 ATOM 2705 0 SER H 76 ATOM 2706 N SER H 77 ATOM 2708 CA SER H 77 ATOM 2709 GB SER H 77 ATOM 2710 OG SER H 77 ATOM 2712 C SER H 77 ATOM 2713 0 SER H 77 ATOM 2714 N VAL H78 ATOM 2716 CA VAL H 78 ATOM 2717 GB VAL H 78 ATOM 2718 CGI VAL H 78 ATOM 2719 CG2 VAL H 78 ATOM 2720 C VAL H 78 ATOM 2721 0 VAL H 78 ATOM 2722 N TYR H 79 ATOM 2724 CA TYR H 79 ATOM 2725 GB TYR H 79 ATOM 2726 CG TYR H 79 ATOM 2727 CD I TYR H 79 ATOM 2728 GEI TYR H 79 ATOM 2729 CD2 TYR H 79 ATOM 2730 CE2 TYR H 79 ATOM 2731 CZ TYR H 79 ATOM 2732 OH TYR H 79 ATOM 2734 C TYR H 79 ATOM 2735 0 TYR H 79 ATOM 2736 N LEU H 80 ATOM 2738 CA LEU H 80 ATOM 2739 CB LEU H 80 ATOM 2740 CG LEU H 80 ATOM 2741 CDI LEU H 80 ATOM 2742 CD2 LEU H 80 ATOM 2743 C LEU H 80 ATOM 2744 0 LEU H 80 ATOM 2745 N GLN H 81 ATOM 2747 CA GLN H 81 ATOM 2748 GB GLN H 81 ATOM 2749 CG GLN H 81 ATOM 2750 CD GLN H 81 ATOM 2751 OEI GLN H 81 ATOM 2752 NE2 GLN H 81 ATOM 2755 C GLN H 81 7.806 -22.025 -5.060 1.00 20.59 6.859 -2 1.536 7.170 -22.240 7.169 -23.755 8.092 -24.404 7.990 -25.915 6.6 12 -26.394 -4.058 -2.730 -2.843 -1.815 -1.886 -1.547 6.895 -20.023 -3.852 6.150 -19.485 -3.012 7.738 -19.325 -4.592 7.840 -17.868 -4.4 12 6.519 -17.188 -4.729 6.400 -16.854 -6.090 8.150 -17.583 -2.961 7.560 -16.691 -2.397 9.072 -18.354 -2.371 9.328 -18.216 0.955 8.642 -19.362 -0.220 7.217 -19.321 -0.35 10.798 -18.2 13 -0.655 11.586 -18.831 -1.383 11.174 -17.444 0.375 12.553 -17.452 0.90 13.271 -16.054 0.77 12.610 -15.007 1.61 14.718 -16.159 1.1: 12.442 -17.927 2.373 11.348 -17.873 2.94( 13.512 -18.464 2.94 1.00 22.07 1.00 22.73 1.00 30.86 1.00 34.56 1.00 36.81 1.00 38.63 1.00 21.01 1.00 18.31 1.00 18.64 1.00 16.65 1.00 18.03 I1.00 23.00 1.00 15.08 1.00 13.71 1.00 12.40 1.00 11.32 I1.00 5.62 1.00 11.83 1.00 11.23 1.00 10.52 1.00 11.36 3 1.00 9.82 5 1.00 2.05 02 1.00 8.95 31 1.00 6.47 11.00 10.77 5 1.00 10.22 I1.00 9.85 3 1.00 11.42 6 1.00 8.95 12 1.00 9.83 90 1.00 13.08 .7 1.00 13.31 16 1.00 16.54 53 1.00 13.14 8 1.00 15.87 .7 1.0021.63 2 1.00 8.87 2 1.00 7.96 4 1.00 7.68 74 1.00 6.13 Z6 1.00 3.75 74 1.00 5.89 13.408 -19.077 13.281 -20.600 12.220 -21.110 10.886 -2 1.256 9.933 -21,792 12.565 -2 1.505 11.642 -22.044 10.327 -22.200 9.440 -22.907 14.656 -18.799 15.682 -18.508 14.563 -18.863 15.756 -18.731 15.865 -17.319 17.161 -17.024 18.360 -16.785 16.965 -15.789 15.717 -19.812 14.834 -19.823 16.636 -20.703 16.809 -21.750 17.433 -22.959 17.864 -24.103 16.700 -24.584 4.28 4.15 3 .20 3.5 2.72 1.9 1.0: 1.45 0.64 5.07: 4.48: 6.41~ 7.9 8.7' 7.857 1.00 7.66 9.665 1.00 7.64 8.384 1.00 6.11 9.2 12 8.3 14 9.279 8.585 9.486 10.25 1.00 10.81 1.00 9.34 I1.00 7.35 1.00 10.80 1.00 7.67 5 1.00 12.30 15.667 -24.853 9.682 1.00 9.50 16.834 -24.650 11.577 1.00 14.89 17.760 -2 1.249 10.279 1.00 7.63 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -252-

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2756 2757 2759 2760 2761 2762 2763 2764 2765 2766 2768 2769 2770 2771 2772 2775 2776 2777 2779 2780 2781 2782 2783 2786 2787 2788 2790 2791 2792 2793 2794 2795 2796 2797 2799 2800 2801 2802 2803 2805 2806 2809 2812 2813 2814 2816 2817 2818 2819 2820 2822 2823 2824 2825 2826 2M2 0 GLN H81 N MET H82 CA MET H 82 CB MET H 82 CG MET H 82 SD METHR 82 CE MET H 82 C MET H 82 O MET H 82 N ASN H 82A CA ASNI-H 82A CB ASN H 82A CG ASN H 82A ODI ASN H 82A ND2 ASN H 82A C ASN H82A O ASN H 82A N ASN H82B CA ASN H 82B GB ASN H 82B CG ASN H 82B ODI ASN H 82B ND2 ASN H 82B C ASN H 82B O ASN H 82B N LEU H 82C CA LEU H 82C GB LEU H 82C CG LEU H 82C CDI LEU H 82C CD2 LEU H 82C C LEU H 82C O LEU H 82C N ARG H 83 8.905 -20.980 9.946 1.00 6.37 17.330 -21.109 11.519 1.00 8.18 18.239 -20.590 12.561 1.00 8.53 17.585 -19.400 13.268 1.00 11 .01 17.055 -18.374 12.3 12 1.00 12.29 15.951 -17.219 13.067 1.00 13.74 14.487 -18.141 12.822 1.00 14.37 18.515 -21.680 13.589 1.00 8.43 17.572 -22.280 14.081 1.00 5.71 19.781 -21.872 13.891 1.00 8.95 20.234 -22.884 14.806 1.00 11.83 21.152 -23.876 14.109 1.00 14.31 20.457 -24.638 13.025 1.00 14.14 19.230 -24.729 13.011 1.00 20.53 21.227 -25.160 12.091 1.00 19.33 21.065 -22.233 1 21.572 -21.134 1 21.234 -22.937 1 22.093 -22.461 23.592 -22.660 23.893 -24.013 23.763 -25.120 24.3 10 -23.938 2 1.755 -20.982 1 22.626 -20.117 1 20.438 -20.717 1 19.930 -19.385 18.398 -19.413 17.778 -19.383 5.867 5.663 6.970 18.068 17.695 16.977 17.54( 15.71 8.401 8.539 8.487 18.761 18.672 17.253 1.00 14.07 1.00 12.90 1.00 13.76 1.00 17.95 1.00 20.73 1.00 29.83 0 1.0032.41 1 1.00 33.10 1.00 15.91 1.00 12.49 1.00 14.84 1.00 13.25 1.00 7.42 1.00 7.73 16.299 -19.736 17.262 1.00 4.66 17.929 -18.000 16.670 1.00 2.94 20.463 -18.841 20.118 1.00 16.15 20.746 -19.599 21.059 1.00 17.22 20.662 -17.536 20.166 1.00 16.23 CA ARG H 83 GB ARG H 83 CG ARG H 83 CD ARG H 83 NE ARG H 83 CZ ARG H 83 NHI ARG H 83 NH2 ARG H 83 C ARG H 83 O ARG H83 N ALA H84 CA ALA H 84 GB ALA H 84 C ALA H 84 O ALA H 84 N ALA H85 CA ALA H 85 GB ALA H 85 C ALA HB8 O ALAI-H 85 N ASP H86 CA ASP H 86 2 1.172 -16.854 22.493 -16.228 23.517 -17.164 24.663 -16.327 25.731 -17.110 26.727 -16.556 2 1.323 20.989 20.447 19.937 19.366 18.689 1.00 16.47 1.00 17.57 1.00 23.38 1.00 29.30 1.00 30.53 1.00 33.66 27.699 -17.323 18.213 1.00 37.56 26.754 -15.227 18.483 1.00 35.33 20.209 -15.733 21.680 1.00 17.82 19.500 -15.237 20.805 1.00 19.55 20.198 -15.271 22.920 1.00 14.91 19.259 -14.191 23.263 1.00 16.48 19.353 -13.846 24.737 1.00 15.35 19.489 -12.925 22.398 1.00 14.44 18.540 -12.166 22.124 1.00 16.17 20.743 -12.729 21.953 1.00 15.72 21.087 -11.588 21.103 1.00 15.91 22.610 -11.473 20.964 1.00 11.61 20.428 -11.685 19.703 1.00 15.42 20.460 -10.694 18.938 1.00 14.28 19.859 -12.870 19.362 1.00 12.78 19.166 -13.055 18.066 1.00 10.42 SUBSTITE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 3-

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2829 2830 2831 2832 2833 2834 2835 2837 2838 2839 2841 2842 2843 2844 2846 2847 2848 2849 2851 2852 2853 2854 2855 2856 2857 2858 2860 2861 2862 2863 2864 2865 2866 2867 2868 2870 2871 2872 2874 2875 2876 2877 2878 2879 2880 2881 2882 2884 2885 288f 2881 288 289( 289 289 289 GB ASP H 86 CG ASP H 86 ODI ASP H 86 0D2 ASP H 86 C ASP H86 O ASP H 86 N THR H 87 CA THR H 87 GB THR H 87 OG ITHR H 87 CG2 THR H 87 C THR H 87 O THR H 87 N GLY H88 CA GLY H 88 C GLY H 88 O GLY H88 N ILE H 89 CA ILE H 89 CB ILE H 89 CG2 ILE H 89 CG I ILE H 89 CD ILE H 89 C ILE H 89 0 ILE H 89 N TYR H90 CA TYR H 90 GB TYR H 90 CG TYR H 90 CDI TYR H 90 GEl TYR H 90 CD2 TYR H 90 CE2 TYR H 90 CZ TYR H 90 OH TYR H 90 C TYR H 90 0 TYR H 90 N TYRH 91 CA TYR H 91 CB TYR H 91 CG TYRKH 91 CDI TYR H 91 CEl TYR H 91 CD2 TYR H 91 ICE2 TYR H 91 CZ TYR H 91 OH TYR H 91 IC TYR H 91 0 TYR H 91 19.191 -14.501 17.595 1.00 4.96 20.581 -15.025 17.414 1.00 10.01 20.814 -16.181 17.786 1.00 12.26 21.440 -14.291 16.916 1.00 8.11 17.735 -12.629 18.149 1.00 8.78 17.003 -12.673 17.172 1.00 12.52 17.316 -12.239 19.320 1.00 8.30 15.948 -11.788 19.506 1.00 8.21 15.713 -11.445 21.041 1.00 7.33 15.904 -12.634 21.815 1.00 6.98 14.316 -10.935 21.301 1.00 5.67 15.688 -10.568 18.601 1.00 9.42 16.564 -9.721 18.445 1.00 13.23 14.534 -10.520 17.972 1.00 7.71 14.200 -9.359 17.178 1.00 9.10 13.112 -9.674 16.231 1.00 9.84 12.640-10.813 16.227 1.00 7.86 12.641 -8.653 15.476 1.00 9.11 11.638 -8.868 14.444 1.00 10.31 10.773 -7.624 14.277 1.00 11.02 9.706 -7.876 13.226 1.00 10.51 10.139 -7.299 15.641 1.00 11.28 9.326 -6.014 15.674 1.00 17.09 12.393 -9.160 13.141 1.00 11.03 13.338 -8.436 12.810 1.00 11.03 12.054 -10.278 12.480 1.00 11.24 12.766 -10.682 13.153 -12.144 14.367 -12.437 14.304 -12.3 17 15.398 -12.607 15.562 -12.865 16.660 -13.156 16.559 -13.011 17.670 -13.217 11.941 -10.411 1 10.768 -10.839 12.555 -9.661 9 11.882 -9*261 11.971 -7.724 11.501 -6.909 10.187 -6.477 9.726 -5.715 12.367 -6.566 11.904 -5.806 10.578 -5.389 10.097 -4.640 12.596 -9.868 13.819 -9.926 11.858 -10.361 12.499 -10.597 11.868 -11.756 10.125 -11.557 12.263 -9.318 11.176 -8.703 13.236 -8.917 11.279 1.00 9.58 11.352 1.00 4.73 12.228 1.00 4.17 13.632 1.00 2.00 14.428 1.00 2.00 11.673 1.00 2.40 12.473 1.00 2.17 13.862 1.00 2.00 14.659 1.00 2.45 0.053 1.00 9.22 9.955 1.00 12.19 ~.125 1.00 8.92 7.869 1.00 6.94 7.693 1.00 8.51 8.859 1.00 7.13 8.923 1.00 6.14 9.997 1.00 7.31 9.890 1.00 4.90 10.978 1.00 8.04 11.017 1.00 5.99 12.115 1.00 13.80 6.640 1.00 5.68 6.618 1.00 10.68 5.661 1.00 5.92 4.354 1.00 9.62 3.624 1.00 8.20 3.662 1.00 16.35 3.528 1.00 7.60 3.579 1.00 8.00 2.785 1.00 8.87 3 CYSH5 CYS H CYS H CYS H CYS H CYS H THR H SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -2 54-

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2895 2896 2897 2899 2900 2901 2902 2904 2905 2906 2907 2909 2910 2911 2912 2913 2914 2915 2917 2918 2919 2920 2922 2923 2924 2925 2926 2927 2930 2931 2932 2934 2935 2936 2937 2938 2939 2940 2941 2942 2943 2944 2946 2947 2948 2949 2950 2952 2953 2954 2955 2956 2957 2958 2959 2960 CA THR H 93 GB THR H 93 OG ITHR H 93 CG2 THR H 93 C THR H93 O THR H93 N GLY H94 CA GLY H 94 C GLY H94 0 GLY H94 N VALH 95 CA VAL H 95 GB VALI-H 95 CG1 VAL H 95 CG2 VAL H 95 C VAL H95 O VALH 95 N GLY H96 CA GLY H 96 C GLY H96 O GLY H96 N GLN H97 CA GLN H 97 GB GLN H 97 CG GLN H 97 CD GLN H 97 OEI GLN H 97 NE2 GLN H 97 C GLN H97 O GLN H97 N PHE H98 CA PHE H 98 GB PHE H 98 CG PHE H 98 CDI PHE H 98 CD2 PHE H 98 GEl PHE H 98 CE2 PHE H 98 CZ PHE H 98 C PHE H98 13.120 -7.666 2.031 1.00 9.75 13.581 -6.438 2.904 1.00 7.13 13.889 -5.309 2.059 1.00 8.11 14.789 -6.775 3.729 1.00 6.38 13.983 -7.740 0.786 1.00 9.01 15.024 -8.385 0.836 1.00 8.92 13.559 -7.104 -0.319 1.00 8.19 14.395 -7.122 -1.486 1.00 9.97 13.962 -6.132 -2.539 1.00 11.34 13.054 -5.370 -2.318 1.00 8.22 14.679 -6.169 -3.673 1.00 13.48 14.454 -5.327 -4.858 1.00 10.59 13.009 -5.252 -5.284 1.00 9.92 12.943 -4.469 -6.574 1.00 12.93 12.412 -6.635 -5.491 1.00 12.57 14.985 -3.907 -4.740 1.00 12.91 14.407 -3.047 -4.075 1.00 16.60 16.113 -3.695 -5.364 1.00 14.72 16.722 -2.351 -5.505 1.00 17.50 16.912 -1.389 -4.282 1.00 15.41 16.467 -0.233 -4.348 1.00 16.20 17.515 -1.782 -3.162 1.00 13.46 17.931 -3.133 -2.860 1.00 13.51 19.415 -3.173 -2.470 1.00 11.95 20.392 -3.138 -3.645 1.00 15.05 20.369 -1.859 -4.476 1.00 16.43 20.832 -0.809 -4.044 1.00 17.08 19.846 -1.954 -5.688 1.00 18.31 17.061 -3.628 -1.680 1.00 10.81 17.109 -4.795 -1.297 1.00 8.86 16.237 -2.728 -1.153 1.00 8.60 15.365 -3.030 -0.021 1.00 8.66 16.024 -2.558 1.275 1.00 11.54 17.333 -3.213 1.620 1.00 9.16 17.356 -4.439 2.271 1.00 6.51 18.544 -2.603 1.305 1.00 9.14 18.564 -5.059 2.603 1.00 9.69 19.744 -3.211 1.639 1.00 8.35 19.759 -4.454 2.296 1.00 6.22 14.056 -2.275 -0.180 1.00 10.16 13.588 -1.638 0.747 1.00 11.80 13.468 -2.339 -1.351 1.00 9.29 12.252 -1.628 -1.609 1.00 8.04 11.995 -1.543 -3.099 1.00 6.69 11.071 -2.292 -0.957 1.00 11.49 10.138 -1.589 -0.533 1.00 11.63 11.105 -3.644 -0.910 1.00 8.89 9.998 -4.423 -0.366 1.00 13.48 9.584 -5.528 -1.335 1.00 17.64 9.293 -5.047 -2.725 1.00 19.49 8.791 -3.766 -2.940 1.00 19.65 8.480 -3.313 -4.208 1.00 19.68 9.490 -5.879 -3.831 1.0021.83 9.178 -5.422 -5.110 1.0024.66 8.667 -4.140 -5.282 1.00 21.57 8.253 -3.720 -6.536 1.00 29.25 O PHE H98 N ALA H 101 CA ALA H 101 GB ALA H 101 C ALA H 101 O ALA H101 N TYR H 102 GA TYR H 102 GB TYR H 102 CG TYR H 102 CD I TYR H 102 GElI TYR H 102 GD2 TYR H 102 GE2 TYR H 102 CZ TYR H 102 OH TYR H 102 SUBSTITUTE SHEET (RULE WO 99/10379 PCT/GB98/02542 -255-

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2962 2963 2964 2966 2967 2968 2969 2970 2971 2972 2973 2975 2976 2977 2978 2979 2980 2982 2983 2984 2985 2987 2988 2989 2990 2991 2992 2995 2996 2997 2999 3000 3001 3002 3004 3005 3006 3008 3009 3010 3011 3013 3014 3015 3017 3018 3019 3020 3022 3023 3024 3025 302( 3027 3028 303( C TYR H 102 O TYRH 102 N TRPH 103 CA TRP H 103 CB TRP H 103 CG TRP H 103 CD2 TRP H 103 CE2 TRP H 103 CE3 TRP H 103 CD1 TRP H 103 NEI TRP H 103 CZ2 TRP H 103 CZ3 TRP H 103 CH2 TRP H 103 C TRPH 103 O TRPH 103 N GLYH 104 CA GLY H 104 C GLYH 104 O GLY H 104 N GLN H 105 CA GLN H 105 CB GLN H 105 CG GLN H 105 CD GLN H 105 OEl GLN H 105 NE2 GLN H 105 C GLNH 105 O GLNH 105 N GLYH 106 CA GLY H 106 C GLYH 106 O GLYH 106 N THRH 107 CA THR H 107 CB THR H 107 OG1 THR H 107 CG2 THR H 107 C THRH 107 O THRH 107 N THRH 108 CA THR H 108 CB THR H 108 OG1 THR H 108 CG2 THR H 108 C THRH 108 0O THRH 108 N VALH 109 CA VAL H 109 CB VAL H 109 SCG1 VALH 109 CG2 VAL H 109 SC VAL H 109 10 VAL H 109 8 N THR H 110 CA THRH 110 10.402 -5.063 11.504 -5.604 9.509 -4.971 9.710 -5.489 9.957 -4.323 11.277 -3.615 12.428 -3.716 13.445 -2.949 12.677 -4.386 11.664 -2.792 12.945 -2.407 14.706 -2.828 13.905 -4.272 14.916 -3.504 0.928 1.00 10.63 1.031 1.00 10.52 .883 1.00 12.90 3.242 1.00 12.06 4.251 1.00 10.97 4.121 1.00 7.64 5.024 1.00 7.34 4.472 1.00 2.00 6.241 1.00 2.00 3.104 1.00 2.00 3.329 1.00 5.49 5.070 1.00 6.14 6.837 1.00 4.72 6.262 1.00 4.93 8.426 -6.189 3.650 1.00 10.58 7.324 -5.684 3.357 1.00 12.28 8.524 -7.363 7.304 -7.969 6.887 -7.282 7.519 -6.295 5.863 -7.817 5.373 -7.251 3.904 -7.694 3.722 -9.067 4.264 1.00 9.92 4.775 1.00 8.86 6.081 1.00 11.03 6.494 1.00 7.62 6.742 1.00 14.11 8.007 1.00 13.52 8.265 1.00 16.08 8.895 1.00 16.34 4.141 -10.239 8.024 1.00 17.73 4.224-10.145 6.813 1.0021.14 4.400 -11.364 8.646 1.00 22.59 6.276 -7.602 9.188 1.00 13.99 6.240 -6.925 10.216 1.00 12.82 7.111 -8.648 9.017 1.00 13.67 8.029 -9.065 10.056 1.00 11.11 7.439-10.154 10.931 1.00 12.32 6.213-10.270 11.084 1.00 11.02 8.301 -10.977 11.484 1.00 14.65 7.855 -12.055 12.387 1.00 12.73 7.902-13.416 11.638 1.00 10.15 7.382-14.453 12.483 1.00 15.55 9.304-13.766 11.191 1.00 4.69 8.745 -12.027 13.618 1.00 10.17 9.944-11.924 13.479 1.00 10.87 8.179-12.063 14.843 1.00 12.24 9.039-11.937 16.025 1.00 10.94 8.360-11.094 17.205 1.00 12.32 9.224-10.934 18.347 1.00 13.78 7.088-11.693 17.677 1.00 15.73 9.605 -13.274 16.492 1.00 9.14 8.933-14.316 16.539 1.00 6.78 10.865-13.225 16.754 1.00 8.85 11.605 -14.332 17.261 1.00 9.39 12.788-14.662 16.322 1.00 11.58 13.739-15.639 16.980 1.00 5.51 12.268-15.232 14.986 1.00 10.69 12.174-13.883 18.589 1.00 12.15 12.926-12.926 18.623 1.00 12.01 11.781 -14.552 19.681 1.00 11.46 12.306-14.238 21.009 1.00 11.24 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -256-

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3031 3032 3034 3035 3036 3037 3039 3040 3041 3042 3043 3044 3045 3047 3048 3049 3051 3052 3053 3055 3056 3057 3059 3060 3061 3063 3064 3065 3066 3067 3069 3070 3071 3072 3073 3074 3078 3079 3080 3082 3083 3084 3086 3087 3088 3089 3091 3092 3093 3095 3096 3097 3098 3099 3100 3101 CB, THR H 110 OGI THRH 110 CG2THRH 110 C THRH I10 O THRH Ii0 N VALH III CA VALH 111 CB VAL H III CG1 VALH III CG2 VAL H III C VALHIII O VALH Ill N SERH 112 CA SERH 112 CB SER H 112 OG SER H 112 C SERH 112 O SERH 112 N SERH 113 CA SER H I 13 CB SER H 113 OG SER H 113 C SERH 113 O SERH 113 N ALAH 114 CA ALA H 114 CB ALA H 114 C ALAH 114 O ALAH 114 N LYSH 115 CA LYS H 115 CB LYS H 115 CG LYS H 115 CD LYS H 115 CE LYS H 115 NZ LYS H 115 C LYSH 115 O LYSH 115 N THRH 116 CA THRH 116 CB THR H 116 OGI THR H 116 CG2 THR H 116 C THRH 116 O THRH 116 N THRH 117 CA THR H 117 CB THRH 117 OGI THRH 117 CG2THRH 117 C THRH 117 O THRH 117 N PROH 118 CD PRO H 118 CA PRO H 118 CB PROH 118 11.175 -14.040 22.044 1.00 9.63 10.211-13.106 21.552 1.00 10.83 11.749-13.553 23.348 1.00 8.99 13.132-15.399 21.501 1.00 7.60 12.632-16.511 21.519 1.0012.38 14.366 -15.155 21.840 1.00 9.00 15.217-16.191 22.409 1.00 12.99 16.629-16.276 21.720 1.00 10.01 17.395 -17.471 22.276 1.00 8.99 16.484-16.393 20.188 1.00 14.22 15.450-15.894 23.907 1.00 13.42 16.248-15.046 24.261 1.00 14.03 14.814-16.628 24.769 1.00 15.10 15.002-16.385 26.179 1.00 17.45 13.877-15.495 26.689 1.00 17.57 14.108-15.154 28.028 1.00 18.71 14.966-17.673 26.950 1.00 18.74 14.128-18.522 26.691 1.00 21.32 15.847 -17.807 27.923 1.00 22.03 15.786-18.966 28.831 1.0026.34 17.195-19.287 29.323 1.00 28.00 17.820-18.122 29.857 1.0035.95 14.807 -18.758 30.055 1.00 26.98 14.655 -19.664 30.898 1.00 26.75 14.139-17.579 30.126 1.0025.34 13.236-17.259 31.225 1.0023.14 12.850-15.782 31.187 1.00 22.38 11.977-18.116 31.207 1.00 24.60 11.432-18.441 30.128 1.0024.23 11.502 -18.459 32.429 1.00 23.35 10.298-19.260 10.436 -20.151 11.651 -21.034 11.555-22.124 12.681 -23.149 12.625 -24.161 32.595 33.818 33.784 34.846 34.714 35.810 1.00 23.70 1.00 24.56 1.00 31.61 1.00 37.03 1.00 36.28 1.00 37.66 9.075 -18.376 32.767 1.00 21.83 9.186-17.219 33.163 1.00 19.35 7.896 -18.924 32.501 1.00 22.54 6.699-18.136 32.650 1.00 25.02 5.433 -18.954 32.354 1.00 28.05 5.489-19.417 30.987 1.00 31.99 4.169-18.118-32.551 1.0025.98 6.669-17.593 34.044 1.00 23.95 7.081-18.264 34.978 1.00 23.92 6.245 -16.372 34.180 1.00 24.46 6.273 -15.699 35.474 1.00 22.17 7.625 -14.999 35.667 1.00 22.94 8.689-15.967 35.507 1.00 19.91 7.726-14.360 37.046 1.00 25.03 5.154-14.681 35.507 1.0022.41 5.049-13.810 34.631 1.0022.33 4.248-14.801 36.473 1.0021.47 4.278-15.766 37.615 1.0024.37 3.142-13.877 36.594 1.00 19.44 2.234-14.580 37.605 1.0021.47 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 7- ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM3

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1102 C 1103 C 1104 0 1105 N 1106 C 1107 C 1108 C 1109 C 1110 C 3111 C 3112 N% 3114 C 3115 C 3116 C 3118 C 3119 C 3120 C 3121 1, 3123 C 3124 C 3125 C 3126 C 3127 C 3128 C 3129 3131 C 3132 3133C 3134( 3135( 3136 3137 3138 3139 3141 31424 31431 3144 3145 3146 3147 31t48 3149 3150 3152 3153 3154 3155 3156 3157 3158 3159 3161 3162 3163 3164 G PRO H 118 PRO H 118 PRO H 118 PRORH 119 D PRO H 119 A PRO H 119 B PRO H 119 G0 PRO H 119 PRO H 119 PRO H- 119 ITHRI-H 120 A THR H 120 B THR H 120 )GI THRH 120 G32THR H 120 THR H 120 THR H- 120 VAL H- 121 ~A VAL H 121 ~B VAL H 121 GI1 VAL H 121 2G2 VAL H 121 VAL H 121 )VAL H 121 STYR H 122 2A TYR H 122 2B TYR H 122 'G TYR H 122 'D1I TYR H 122 "EI TYR H 122 ,D2 TYR H 122 :E2 TYR H 122 :Z TYR H 122 DH TYR H 122 CTYR H 122 0 TYR H 122 N PRO H 123 CD PRO H 123 CA PRO H 123 3.232 -15.199 38.533 1.00 23.59 3.743 -12.587 37.106 1.00 16.22 4.806 -12.611 37.749 1.00 13.84 3.163 -11.443 36.804 1.00 14.35 1.953 -11.227 35.990 1.00 14.96 3.728 -10.184 37.275 1.00 14.79 3.056 -9.164 1.696 -9.745 3.377 -9.958 2.303 -10.393 4.256 -9.3 14 3.845 -8.837 4.977 -8.765 36.380 36.220 3 8.7 16 39. 166 39.447 40.761 4 1.775 1.00 13.18 1.00 13.05 1.00 13.65 1.00 14.64 1.00 13.96 1.00 12.82 1.00 5.50 5.844 -7.751 41.415 1.00 20.74 5.757 -10.030 4 1.829 1.00 8.80 3.33 1 -7.469 40.486 1.00 8.85 4.041 -6.675 39.868 1.00 10.44 2.070 -7.221 40.800 1.00 11.59 1.455 -5.913 40.491 1.00 8.52 0.016 -6.087 40.012 1.00 6.26 -0.604 -4.736 39.688 1.00 3.84 0.020 -6.995 38.800 1.00 9.50 1.505 -4.970 41.692 1.00 12.01 1.230 -5.376 42.828 1.00 10.41 1.888 -3.726 41.451 1.00 11.35 2.097 -2.781 42.546 1.00 11.02 3.596 -2.477 42.719 1.00 7.81 4.43 5 -3.676 4.108 -4.421 4.872 -5.516 5.555 -4.061 6.327 -5.142 5.989 -5.868 6.829 -6.861 43. 129 44.284 44.695 42.394 42.788 43.948 44.411 12.256 t 1.204 13.196 1.00 15.44 1.00 16.70 1.00 12.55 1.00 7.91 1.00 8.28 1.00 11.52 1.00 11.02 1.00 12.61 1.00 11.44 1.00 18.80 1.367 1.477 0.6 15 -1.517 -0.956 -1.027 CB PRO H 123 CG PRO H 123 C PRO H 123 O PRO H 123 N LEU H 124 CA LEU H 124 CB LEU H 124 CG LEU H 124 CD I LEU H 124 CD2 LEU H 124 C LEU H 124 O LEU H 124 N ALA H 125 CA ALA H 125 CB ALA H 125 C ALA H 125 0 ALA H 125 0.495 -1.532 44.586 1.00 19.13 -0.158 0.199 43.018 1.00 18.57 1. 108 0.142 44.202 1.00 15.86 -0.200 -0.377 45.251 1.00 19.34 0.767 1.387 43.094 1.00 18.37 1.745 1.372 43.851 1.00 24.31 0.492 2.394 42.302 1.00 17.89 1.279 3.607 42.355 1.00 18.57 1.976 3.884 41.033 1.00 17.71 2.958 2.8 12 40.543 1.00 20.67 3.674 3.321 39.3 17 1.00 18.20 3.932 2.391 41.659 1.00 18.24 0.402 4.788 42.763 1.00 18.06 -0.459 5.263 41.988 0.575 5.193 44.024 -0.181 6.299 44.57f -0.606 6.005 46.01f 0.678 7.528 44.508 1.893 7.435 44.519 1.00 14.26 1.00 18.65 i1.00 16.82 1.00 13.74 1.00 15.68 1.00 16.41 SUBSTITUTE SHEET (RULE 2B) WO 99/10379 WO 99/ 0379PCT/GB98/02542 *-258-

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3165 3166 3167 3168 3169 3170 3172 3174 3175 3176 3177 3178 3179 3 180 3183 3185 3186 3188 3189 3190 3191 3192 3193 3194 3195 3197 3198 3199 3200 3201 3202 3203 3205 3206 3207 3209 3210 3211 3212 3214 3215 3216 3217 3218 3219 3220 3221 3223 3224 3225 3226 322 322S 323( 323 N PRO H 126 CD PRO H 126 CA PRO H 126 GB PRO H 126 CG PRO H 126 C PRO H 126 O PRO H 126 N GLYKH 127 CA GLY H 127 C GLY H 127 OTI GLY H 127 0T2 GLY H 127 GB ALA H- 134 C ALA H 134 0 ALA H 134 N ALA H 134 CA ALA H 134 N MET H 135 CA METI-H 135 GB MET H 135 CG MET H 135 SD MET H 135 CE MET H 135 C MET H 135 0 MET H 135 N VALHI136 CA VAL H 136 GB VAL H 136 CGlI VAL H 136 CG2 VAL H 136 C VAL H 136 O VAL H 136 N THRH 137 CA THR H 137 GB THR H 137 OG I THR H 137 CG2 THR H 137 C THR H 137 0 THR H 137 N LEU H 138 CA LEU H 13 8 GB LEUHN 138 CG LEU H 138 CDI LEU H 138 GD2 LEU H 138 C LEUHI138 0 LEUHI138 N GLY H 139 GA GLY H 139 ~C GLY H 39 0O GLYHI139 N CYSHI140 ICA CYS H 140 GB CYS H 140 SG GYS H 140 1 C CYS H 140 0.066 8.687 44.406 1.00 16.40 -1.408 8.891 44.357 1.00 13.85 0.790 9.954 44.329 1.00 16.02 -0.346 10.988 44.293 1.00 15.53 -1.468 10.210 43.677 1.00 14.07 1.753 10.168 45.504 1.00 18.31 1.470 9.847 46.678 1.00 16.34 2.898 10.680 45.169 1.00 22.48 3.870 10.970 46.171 1.00 30.63 3.658 12.353 46.704 1.00 33.75 4.436 13.259 46.288 1.00 39.27 2.699 12.543 47.5 15 1.00 35.28 -7.913 19.970 39.281 1.00 21.74 -8.371 17.522 39.464 1.00 25.40 -9.444 16.941 39.284 1.00 26.02 -7.293 18.763 41.334 1.00 24.67 -8.300 18.856 40.227 1.00 23.36 -7.220 17.078 38.992 1.00 24.22 -7.086 -6.690 -7.856 -8.959 -8.963 -5.970 -5.013 -6.072 -5.000 -5.421 -6.664 -4.273 -4.563 -5.405 -3.256 -2.783 -1.7 16 -2.29 -1.31( -2.294 -1.419 -2.933 -2.625 -3.906 -4.695 1 1

I

15 .795 15.998 16. 182 [4.726 14.248 5.087 5.747 3.787 13 .075 12.616 38.331 36.848 35. 864 35.832 34. 1 04 39.063 39.498 39.250 39.925 4 1.358 1.00 26.09 1.00 30.45 1.00 34.99 1.00 46.83 1.00 42.78 1.00 25.74 1.00 25.90 1.00 22.09 1.00 18.97 1.00 16.24 I11.760 41.344 1.00 15.37 111.897 42.010 1.00 16.51 11.886 39.090 1.00 17.30 11.217 38.482 1.00 17.97 11.641 39.022 1.00 17.82 10.485 38.267 1.00 18.38 10.872 37.253 1.00 15.72 6 11.858 36.377 1.00 16.58 9.661 36.419 1.00 13.21 9.340 39.158 9.5 16 40.024 8.188 38.935 6.956 39.639 6.404 40.218 7.398 41.034 1.00 16.41 1.00 14.38 1.00 13.46 1.00 11.93 1.00 9.54 1.00 9.64 -5.924 6.726 41.571 1.00 11.85 -3.824 7.938 42.158 1.00 6.56 -2.053 5.967 38.641 1.00 12.78 -2.303 6.091 37.448 1.00 10.57 -1.309 5.004 39.097 1.00 11.80 -0.771 4.050 38.164 1.00 11.77 -0.576 2.690 38.756 1.00 14.58 -0.870 2.454 39.927 1.00 14.52 -0.069 1.797 37.952 1.00 13.05 0.194 0.461 38.377 1.00 12.15 -0.944 -0.465 37.972 1.00 15.82 -1.988 -0.926 39.377 1.00 30.05 1.443 -0.023 37.760 1.00 9.66 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 9-

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3232 3233 3235 3236 3237 3238 3239 3240 3241 3242 3244 3245 3246 3247 3248 3249 3250 3252 3253 3254 3255 3256 3257 3261 3262 3263 3265 3266 3267 3268 3270 3271 3272 3273 3274 3275 3276 3277 3278 3280 3281 3282 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 3295 3296 3297 CYS H 140 qJ LEU H 141 -A LEU H 141 B LEU H 141 LEU H 141 :Dl LEU H 141 :'D2 LEU H 141 :LEU H 141 D LEU H 141 q' VAL H 142 C.A VALI-H 142 C.B VAL H 142 CGI VAL H 142 CG2 VAL H 142 CVAL H 142 0 VAL H 142 1.589 0.118 36.543 1.00 8.35 2.338 -0.552 38.590 1.00 6.85 3.558 -1.210 38.113 1.00 10.45 4.732 -1.024 39.080 1.00 3.00 6.079 -1.654 38.695 1.00 7.34 6.582 -1.117 37.363 1.00 7.63 7.118 -1.354 39.745 1.00 2.28 3.311 -2.709 37.952 1.00 9.22 2.869 -3.368 38.884 1.00 8.85 3.557 -3.220 36.756 1.00 10.01 3.455 -4.640 36.485 1.00 7.47 2.615 -4.880 35.208 1.00 10.12 2.384 -6.392 34.957 1.00 8.96 1.282 -4.149 35.351 1.00 6.58 4.883 -5.162 36.345 1.00 11.16 5.512 -5.095 35.254 1.00 6.29 5.398 -5.687 37.452 1.00 9.75 N LYSHI143 CA LYS H 143 CB LYS H 143 CG LYS H 143 CD LYS H 143 CE LYS H 143 NZ LYS H 143 C LYS H 143 0 LYS H 143 N GLY H 144 CA GLY H 144 C GLY H 144 GLY H 144 N TYRH 145 CA TYR H 145 GB TYR H 145 CG TYR H 145 CD I TYR H 145 CElI TYR H 145 CD2 TYR H 145 CE2 TYR H 145 CZ TYR H 145 OH TYR H 145 C TYR H 145 TYR H 145 N PHE H 146 CA PHE H 146 GB PHE H 146 CG PHE H 146 CDI PHE H 146 CD2 PHE H 146 CEI PHE H 146 CE2 PHE H 146 CZ PHE H 146 C PHEMH 146 O PHE H 146 N PRO H 147 CD PRO H 147 CA PRO H 147 CB PRO H 147 6.811 -6.0073 7.354 -5.430 3 8.872 -5.352 3 9.272 -4.908 10.790 -4.927 11.194 -4.987 7.170 -7.505 3~ 6.468 -8.388 3 8.247 -7.741 3 8.889 -9.060 8.106 -10.220 8.220 -11.321 7.371 -10.011 6.630 -11.111 5.217 -10.675 5.137 -9.598 5.411 -8.278 5.280 -7.269 4.728 -9.867 4.598 -8.843 17.531 8.840 18.953 ~0.356 40.5 18 4 1.953 1.00 12.16 1.00 9.61 1.00 9.64 1.00 11.17 1.00 15.36 1.00 13.08 7.404 1.00 14.70 7.894 1.00 17.80 6.666 1.00 16.56 36.589 16.012 36.532 34.931 34.294 33.851 32.797 33. 126 32.194 3 1.485 30.532

I.

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4.879 -7.548 30.902 1 4.820 -6.506 29.978 1 7.389 -11.662 33.088 1 8.389 -11.098 32.669 1 6.931 -12.800 32.589 1 7.455 -13.385 31.3611 8.887 -13.880 3 1.495 1 9.385 -14.479 30.188 10.168 -13.728 29.327 8.957 -15.751 29.761 10.506 -14.210 28.054 9.282 -16.240 28.506 10.054 -15.469 27.644 6.642 -14.565 31.019 1 6.360 -15.333 31.930 1 6.211 -14.757 29.720 1 4.961 -15.458 29.393 6.430 -13.882 28.555 6.205 -14.891 27.401 .00 18.62 00 16.58 00 20.26 00 15.03 .00 12.99 .00 10.99 .00 13.14 .00 15.73 .00 12.07 [.00 15.71 .00 9.54 .00 10.77 .00 9.76 00 13.49 .00 12.72 00 16.82 1.00 18.55 .00 18.86 1.00 23.23 1.00 25.00 1.00 24.90 1.00 26.32 1.00 26.32 1.00 25. 16 .00 19.54 .00 18.10 .00 21.47 1.0021.60 1.00 21.86 1.00 21.39 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -260-

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3298 3299 3300 3301 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3314 3315 3316 3317 3318 3320 3321 3322 3323 3324 3325 3326 3328 3329 3330 3332 3333 3334 3335 3337 3338 3339 3340 3341 3342 3343 3345 334( 334', 334~ 335( 335 335: 335~ 335: 3354 335, 335 335 336 336 CG PRO H 147 C PRO H 147 0 PRO H 147 N GLU H 148 CA GLU H 148 GB3 GLU H 148 CG GLU H 148 GD GLU H 148 OEI GLU H 48 0E2 GLU H 148 C GLU H 148 O GLU H 148 N PRO H 149 CD PRO H 149 CA PRO H 149 GB3 PRO H 149 CG PRO H 149 C PRO H 149 O PRO H 149 N VAL H 150 GA VAL H 150 GB VAL H 150 CGI VAL H 150 GG2 VAL H 150 C VAL H 150 O VAL H 150 N THR H 151 CA THR H 151 GB3 THR H 151 OG I THR H 151 CG2 THR H 151 C THR H 151 0 THRI-H 151 N VAL H 152 GA VAL H 152 GB VAL H 152 4CG I VAL H 152 C G2 VAL H 152 C VAL H 152 0O VALHl152 IN THRHI153 CA THR H 153 GB3 THR H 153 001I THR H 153 GG2 THR H 153 C THRH 153 1 0 THR H 153 2 N TRPHI154 4 GA TRP H 154 5 GB3 TRP H 154 6 CG TRP H 154 7 GD2 TRP H 154 8 GE2 TRP H 154 9 GE3 TRP H 154 0 CDI TRP H 154 1 NEI TRP H 154 5.272 -15.938 28.004 1.00 19.80 5.429 -12.706 28.486 1.00 18.87 4.621 -12.537 29.372 1.00 15.77 5.438 -11.977 27.346 1.00 19.05 4.421 -10.976 27.061 1.00 19.21 4.991 -9.896 26.155 1.00 17.80 6.141 -9.138 26.738 1.00 15.35 6.495 -7.945 25.897 1.00 19.90 7.607 -7.934 25.3 14 1.00-23.72 5.666 -7.006 25.812 1.00 17.13 3.306 -11.661 26.286 1.00 19.80 3.507 -12.759 25.820 1.00 21.47 2.099 -11.079 26.136 1.00 19.34 0.864 -11.830 25.967 1.00 15.47 1.670 -9.808 26.680 1.00 18.47 0.574 -9.440 25.693 1.00 18.21 0.055 -10.797 25.219 1.00 17.16 1. 117 -9.890 28.128 1.00 18.85 1.138 -10.912 28.825 1.00 16.35 0.431 -8.812 28.426 1.00 19.66 -0.234 -8.562 29.666 1.00 16.78 0.808 -7.952 30.654 1.00 16.55 0.424 -6.574 31.111 1.00 17.59 1.049 -8.879 31.803 1.00 13.17 -1.328 -7.578 29.276 1.00 16.49 -1.179 -6.844 28.299 1.00 18.33 -2.454 -7.637 29.908 1.00 14.32 -3.5 18 -6.695 29.627 1.00 14.69 -4.767 -7.415 29.063 1.00 17.81 -5.363 -8.243 30.083 1.00 22.14 -4.366 -8.318 27.887 1.00 20.30 -3.895 -5.975 30.913 1.00 13.72 -4.185 -6.627 31.907 1.00 13.94 -3.914 -4.650 30.867 1.00 12.98 -4.179 -3.838 32.043 1.00 12.73 -2.978 -2.934 32.366 1.00 11.49 -3.293 -2.080 33.597 1.00 11.37 -1.722 -3.768 32.599 1.00 9.03 -5.406 -2.957 31.861 1.00 15.95 -5.471 -2.150 30.915 1.00 19.74 -6.392 -3.130 32.752 1.00 19.44 -7.597 -2.3 15 32.735 1.00 19.80 -8.853 -3.184 32.492 1.00 21.72 -8.787 -4.329 33.329 1.00 26.52 -8.933 -3.640 31.043 1.00 21.56 -7.761 -1.5 16 34.059 1.00 17.98 -7.031 -1.728 35.029 1.00 17.86 -8.689 -0.566 34.061 1.00 18.02 -8.952 -8.433 -6.952 -6.067 -4.758 -76.266 -6.177 -4.866 0.230 1.6 18 1.646 1.823 1.896 1.949 1 .600 1.751 35.234 35.037 34.971 36.081 35.568 37.475 33.856 34.220 1.00 16.37 1.00 15.29 1.00 14.01 1.00 14.22 1.00 12.55 1.00 13.71 1.00 13.72 1.00 14.65 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -26 1-

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3363 3364 3365 3366 3367 3368 3370 3371 3372 33 73 3374 3377 3378 3379 3381 3382 3383 3385 3386 3387 3389 3390 3391 3392 3394 3395 3396 3398 3399 3400 3402 3403 3404 3405 3406 3407 3408 3409 3411 3412 3413 3414 3415 3417 34 1,8 3419 3421 3422 3423 3425 3426 3427 3428 3430 3431 3432 CZ2 TRP H 154 CZ3 TRP H 154 CH2 TRP H 154 C TRP H 154 O TRP H 154 N ASN H 155- CA ASN H 155 GB ASN H 155 CG ASN H 155 ODI ASN H 155 ND2 ASN H 155 C ASN H 155- O ASN H 155 N SER H 156- CA SER H 156 GB SER H 156 00 SER H 156 C SER H 156 SER H 156- N GLY H 157 CA GLY H 157 C GLY H 157 0 GLY H 157 N SERHI158 CA SER H 158 CB SER H 158 00 SER H 158 C SERHI158 0 SERH 158 N LEU H 159 CA LEU H 159 GB LEU H 159 CG LEU H 159 CDI LEU H 159 CD2 LEU H 159 C LEU H 159 0 LEU H 159 N ALA H 160 CA ALA H 160 GB ALA H 160 C ALA H 160 0 ALA H 160 N SER H 161 CA SER H 161 GB SER H 161 OG SER H 161 C SER H 161 O SER H 161 N GLY H 162 CA GLY H 162 C GLYHI162 '0 GLYHI162 N VALHI163 CA VAL H 163 CB VAL H 163 CGI VAL H 163 -3.652 2.096 36.372 1.00 11.60 -5.166 2.157 38.276 1.00 13.74 -3.873 2.232 37.715 1.00 15.50 10.420 0.226 35.491 1.00 16.57 11.208 0.455 34.582 1.00 19.07 .10.778 -0.068 36.722 1.00 18.63 -12.180 -0.281 37.110 1.00 19.34 -12.891 1.048 37.320 1.00 19.07 -12.490 1.668 38.645 1.00 19.37 -11.779 1.057 39.456 1.00 17.72 -12.921 2.889 38.867 1.00 21.85 .12.904 -1.170 36.102 1.00 20.59 .13.986 -0.848 35.618 1.00 19.83 12.24 1 -2.298 35.766 1.00 22.94 -12.750 -3.259 34.796 1.00 23.80 -14.038 -3.890 35.323 1.00 24.08 -13.792 -4.57636.536 1.00 23.19 12.976 -2.658 33.389 1.00 26.88 13.725 -3.203 32.568 1.00 29.20 -12.320 -1.557 33.089 1.00 26.24 -12.519 -0.967 3 1.796 1.00 28.52 -13.571 -13.806 .14.208 -15.168 -16.060 15 .374 .14.409 .14.917 -13.174 0.138 31.791 0.760 30.749 0.382 32.944 1.460 33.047 1.3 13 34.323 1.579 35.535 2.776 33.013 3.781 32.545 2.756 33.524 1.00 28.13 1.00 28.70 1.00 27.82 1.00 27.17 1.00 28.51 1.00 25.88 1.00 27.55 1.00 28.23 1.00 29.42 -12.285 3.894 33.378 1.00 30.68 -11.275 3.969 34.519 1.00 31.18 -11.742 4.647 35.816 1.00 29.87 -10.617 4.653 36.846 1.00 34.45 -12.180 6.062 35.529 1.00 29.03 -11.562 3.691 32.072 1.0031.97 10.552 -12.155 -11.612~ -12.774 -10.777 -9.6 18 -11.364 -10.671 -11.692 -12.991 -9.605 -9.745 -8.540 3.001 32.022 1.00 31.21 4.217 31.009 1.00 34.61 4.062 29.651 1.00 35.80 3.835 28.686 1.00 34.51 5.293 29.237 1.00 35.27 5.185 28.786 1.00 34.38 6.459 29.407 1.00 33.77 7.704 29.107 1.00 33.98 8.842 29.075 1.00 33.96 8.335 28.755 1.00 38.30 7.996 30.175 1.00 30.88 7.604 3 1.345 1.00 32.73 8.664 29.773 1.00 28.58 -7.509 9.053 30.740 1.00 23.36 -6.481 7.985 31.068 1.00 19.44 -5.660 8.182 31.988 1.00 17.19 -6.484 6.886 30.290 1.00 16.90 -5.563 5.790 30.522 1.00 14.28 -6.248 4.447 30.286 1.00 11.19 -5.249 3.311 30.466 1.00 9.55 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -262-

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3433 3434 3435 3436 3438 3439 3440 3441 3442 3444 3445 3447 3448 3449 3451 3452 3453 3455 3456 3457 3458 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 3470 3471 3472 3473 3474 3475 3476 CG2 VAL H 163 C VAL H 163 0 VAL H 163 N HIS H 164 CA HIS H 164 CB HIS H 164 CG HIS H 164 CD2 HIS H 164 NDI HIS H 164 GEl HIS H 164 NE2 HIS H 164 C HIS H 164 0 HIS H 164 N THR H 165 CA THR H 165 C1B THR H 165 OG I THR H 165 CG2 THR H 165 C THR H 165 O THR H 165 N PHE H 166 CA PHE H 166 GB3 PHE H 166 CG PHE H 166 CDI PHE H 166 CD2 PHE H 166 CEl PHE H 166 CE2 PHE H 166 CZ PHE H 166 C PHE H 166 O PHE H 166 N PRO H 167 -7.394 4.309 31.280 1.00 8.14 -4.334 -4.426 -3.208 -1.976 -1.063 -1.358 -1.800 -1.111 1.352 -1.763 5.883 29.638 1.00 16.70 6.310 28.494 1.0020.46 5.502 30.172 1.00 12.44 5.465 29.432 6.591 29.851 7.848 29.188 9.033 29.657 8.037 27.847 9.251 27.488 9.876 28.571 1.00 12.24 1.00 12.04 1.00 17.45 1.00 16.45 1.00 19.78 1.00 18.88 1.00 19.92 PRO H 167 PRO H 167 PRO H 167 PRO H 167 PRO H 167 PRO H 167 -1.262 4.216 29.770 1.00 12.66 -0.943 4.023 30.924 1.00 12.50 -1.030 3.348 28.825 1.00 12.38 -0.208 2.196 29.132 1.00 10.10 -0.949 0.879 28.952 1.00 9.55 -2.152 0.949 29.722 1.00 11.21 -0.115 -0.286 29.439 1.00 8.04 1.042 2.239 28.295 1.00 11.67 0.977 2.443 27.089 1.00 10.32 2.174 2.052 28.974 1.00 11.57 3.499 2.190 28.390 1.00 12.01 4.382 2.951 29.407 1.00 9.65 3.765 4.283 29.822 1.00 8.07 2.849 4.351 30.868 1.00 4.17 4.004 5.456 29.073 1.00 10.68 2.155 5.547 31.155 1.00 8.24 3.3 14 6.654 29.355 1.00 11.02 2.386 6.698 30.394 1.00 5.44 4.116 0.815 28.006 1.00 15.40 3.583 -0.249 28.404 1.00 16.48 5.210 0.826 27.164 1.00 14.51 5.803 2.030 26.521 1.00 14.57 5.919 -0.378 26.684 1.00 13.56 6.884 0.166 25.595 1.00 15.95 6.303 1.479 25.213 1.00 15.19 6.720 -1.095 27.757 1.00 13.70 7.321 -0.457 28.630 1.00 8.91 6.767 -2.424 27.618 1.00 14.48 7.506 -3.277 28.526 1.00 13.11 7.212 -4.746 28.240 1.00 12.04 8.982 -3.020 28.403 1.00 15.12 9.496 -2.687 27.332 1.00 14.20 9.661 -3.093 29.519 1.00 14.23 11.077 -2.965 29.524 1.00 11.53 11.614 -1.828 30.480 1.00 10.77 9 11.381 -0.451 29.880 1.00 5.38 9 10.921 -1.887 31.820 1.00 8.65 11.569 -4.309 29.970 1.00 14.43 10.861 -4.991 30.697 1.00 13.16 12.714 -4.721 29.457 1.00 16.49 13.336 -5.954 29.891 1.00 20.55 13.963 -6.711 28.694 1.00 17.41 14.387 -8.182 28.942 1.00 16.89 0 13.184 -9.004 29.309 1.00 11.20 0 15.058 -8.781 27.707 1.00 13.43 ATOM 3477 N ALA H 168

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3479 3480 3481 3482 3483 3485 3486 3487 3488 3489 3490 3491 3493 3494 3495 3496 3497 CA ALA H 168 CB ALA H 168 C ALAKH 168 o ALA H 168 N VAL H 169 CA VAL H 169 GB3 VAL H 169 CGI VAL H 16' C G2 VAL H 16' C VAL H 169 O VAL H 169 N LEUKH 170 CA LEU H 170 GB LEU H 170 CG LEU H 170 CDI LEU H 174 CD2 LEU H 174 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -263-

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3498 3499 3500 3502 3503 3504 3505 3506 3507 3510 3511 3512 3514 3515 3516 3517 3518 3520 3521 3522 3523 3524 C LEU H 170 0 LEU H 170 N GLN H 171 CA GLN H 171 GB GLN H 171 CG GLN H 171 CD GLN H 171 OEI GLN H 171 NE2 GLN H 171 C GLN H 171 O GLN H 171 N ALA H 172 CA ALA H 172 GB ALA H 172 C ALA H 172 0 ALA H 172 N ALA H 173 CA ALA H 173 GB ALA H 173 C ALA H 173 O ALA H 173 N LEU H 174 14.400 -5.625 30.916 1.00 21.20 15.390 -4.963 30.619 1.00 23.98 3526 CA LEU H 174 3527 GB LEUKH 174 3528 CG LEU H 174 3529 CD I LEU H 174 3530 CD2 LEU H 174 3531 C LEU H 174 3532 0 LEUI-H 174 3533 N TYR H 175 3535 CA TYR H 175 3536 GB TYR H 175 3537 CG TYR H 175 3538 CD1I TYR H 175 3539 GElI TYR H 175 3540 CD2 TYR H 175 3541 CE2 TYR H 175 3542 CZ TYR H 175 3543 OH TYR H 175 3545 C TYR H 175 3546 0 TYR H 175 3547 N THR H 176 3549 CA THR H 176 3550 GB THR H 176 3551 OG1ITHR H 176 3553 CG2 THR H 176 3554 C THR H 176 3555 0 THR H 176 3556 N LEU H 177 3558 CA LEU H 177 3559 CB LEU H 177 3560 CG LEU H 177 3561 CDI LEU H 177 3562 CD2 LEU H 177 3563 C LEU H 177 3564 0 LEU H 177 14.169 -6.028 32.146 1.00 25.48 15.157 -5.823 33.175 1.0027.97 14.916 -4.492 33.962 1.0033.14 13.467 -4.068 34.268 1.0035.78 13.319 -2.530 34.449 1.0041.72 14.162 -1.751 33.979 1.00 43.19 12.253 -2.078 35.114 1.00 39.50 15.230 -7.042 34.083 1.00 30.85 14.312 -7.308 34.873 1.0030.30 16.307 -7.817 33.893 1.00 30.98 16.568 -9.039 34.690 1.00 32.89 16.053 -8.885 36.145 1.00 34.56 15.964 -10.291 34.039 1.0032.42 15.553 -11.239 34.741 1.0033.51 15.982 -10.303 32.683 1.0028.84 15.370 -11.366 31.889 1.00 24.12 15.884 -12.754 32.279 1.00 24.73 13.860 -11.329 32.002 1.0022.90 13.186 -12.169 31.437 1.0024.63 13.314 -10.347 32.714 1.00 19.03 11.868 -10.284 32.897 1.00 16.09 11.502 -10.527 34.386 1.00 13.53 11.823 -11.921 35.008 1.00 13.70 11.399 -11.927 36.487 1.00 13.19 11.093 -13.033 34.243 1.00 7.07 11.366 -8.934 32.444 1.00 11.64 12.095 -7.980 32.520 1.00 13.03 10.153 -8.887 3 1.980 1.00 11.45 9.546 -7.644 3 1.500 1.00 13.69 8.505 -7.917 30.412 1.00 13.82 9.047 -8.559 29.178 1.00 14.75 9.965 -7.890 28.395 1.00 17.41 10.503 -8.454 27.241 1.00 18.34 8.651 -9.827 28.790 1.00 18.01 9.174 -10.408 27.633 1.0020.37 10.106 -9.710 26.864 1.00 19.65 10.628 -10.265 25.726 1.00 21.14 8.8 13 -6.864 32.614 1.00 16.88 8.188 -7.448 33.534 1.00 15.69 8.827 -5.545 32.462 1.00 14.27 8.125 -4.654 3.3.374 1.00 13.28 9.101 -3.932 34.349 1.00 11.07 9.699 -4.857 35.280 1.00 9.99 8.353 -2.855 35.118 1.00 7.94 7.416 -3.584 32.574 1.00 11.40 8.015 -2.999 3 1.677 1.00 10.96 6.156 -3.347 32.837 1.00 9.44 5.528 -2.190 32.216 1.00 11.96 4.765 -2.521 30.918 1.00 12.44 3.542 -3.432 30.927 1.00 13.51 2.348 -2.762 31.611 1.00 16.92 3.176 -3.748 29.478 1.00 19.97 4.689 -1.442 33.231 1.00 11.72 4.664 -1.831 34.398 1.00 12.02 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -264-

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3565 3567 3568 3569 3571 3572 3573 3575 3576 3577 3579 3580 3581 3583 3584 3585 3587 3588 3589 3591 3592 3593 3594 3595 3596 3597 3599 3600 3601 3603 3604 3605 3606 3608 3609 3610 3611 3612 3613 3614 3615 3616 3617 3618 3619 3620 3621 3623 3624 3625 3627 3628 3629 3631 363: 3633 N SER H 178 CA SER H 178 GB SER H 178 OG SER H 178 C SER H 178 O SERI-H 178 N SER H 179 GA SER H 179 GB SER H 179 OG SERI-H 179 C SER H 179 0 SER H 179 N SER H 180 CA SER H 180 GB SER H 180 OG SER H 180 C SER H 180 O SER H 180 N VAL H 181 GA VAL H 181 GB VAL H 181 CG I VAL H 181 GG2 VAL H 181 C VAL H 181 0 VAL H 181 N TH-R H 182 CA THR H 182 GB THR H 182 OG I THR H 182 GG2 THR H 182 G THRI-H 182 O TH-R H 182 N VAL H 183 GA VAL H 183 GB VAL H 183 CGI VAL H 183 GG2 VAL H 183 G VALI-H 183 O VAL H 183 N PRO H 184 4.091 -0.356 32.826 1.00 9.83 3.261 3.993 5.061I 2.068 2.047 1.096 -0.086 -1.225 -2.371 -0.437 0.004 -1.192 -1.629 -0.622 -0.758 -3.039 -3.4 13 -3.841 0.429 33.720 1.00 12.66 1.665 34.273 1.00 16.23 1.325 35.106 1.00 21.15 0.941 32.983 1.00 11.78 0.979 31.760 1.00 12.05 1.333 33.750 1.00 10.09 1.954 33.244 1.00 9.78 0.943 33.162 1.00 7.12 1.448 32.486 1.00 13.99 3.044 34.227 1.00 11.73 3.012 35.394 1.00 10.99 3.999 33.772 1.00 12.62 5.088 34.616 1.00 11.78 6.247 34.486 1.00 15.26 6.938 33.258 1.00 15.98 5.538 34.206 1.00 11.26 5.3 18 33.063 1.00 12.64 6.068 35.170 1.00 12.70 -5.143 6.697 34.893 1.00 12.65 -6.394 6.148 35.602 1.00 14.52 -7.465 5.808 34.616 1.00 8.51 -6.086 5.076 36.606 1.00 15.67 -5.126 8.065 35.510 1.00 13.40 -4.564 8.238 36.571 1.00 10.66 -5.816 8.994 34.864 1.00 15.42 -6.029 10.300 35.418 1.00 12.05 -5.483 11.393 34.504 1.00 12.00 -4.068 11.185 34.369 1.00 12.34 -5.731 12.786 35.097 1.00 10.88 -7.505 10.452 35.623 1.00 15.30 -8.310 10.221 34.702 1.00 15.69 -7.851 10.747 36.872 1.00 15.89 -9.237 10.912 37.302 1.00 15.70 -9.692 9.772 38.276 1.00 13.11 -9.861 8.472 37.519 1.00 16.73 -8.678 9.585 39.374 1.00 7.49 -9.375 12.221 38.050 1.00 14.30 -8.395 12.760 38.5 16 1.00 15.26 -10.592 12.768 38.177 1.00 15.74 11.860 12.255 37.668 1.00 15.39 -10.784 14.007 38.906 1.00 16.30 -12.282 14.289 38.757 1.00 15.06 -12.662 13.516 37.544 1.00 15.56 -10.429 13.704 40.341 1.00 15.62 -10.859 12.707 40.872 1.00 17.90 -9.648 14.527 40.960 1.00 21.17 PRO H 184 PRO H 184 PRO H 184 PRO H 184 PRO H 184 PRO H 184 SER H 185 SER H 185 SER H 185 iSER H 185 SER H 185 SER H 185 SER H 186 SER H 186 1 SER H 186 3 SER H 186 -9.288 -8.371 -8.807 -10.533 -10.466 -11.681 12.880 -14.011 -14.531 14.311 42.3491 15.436 42.815 1 16.685 42.271 14.241 43.255 1 13.737 44.376 1 14.743 42.795 1 14.649 43.614 15.504 43.021 14.972 41.797 1.00 23.69 1.00 26.61 1.00 31.23 .00 26.32 .00 29.50 .00 25.25 1.00 25.46 1.00 26.27 1.00 29.82 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -26

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A-TOM

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3635 3636 3637 3639 3640 3641 3643 3644 3645 3646 3648 3649 3650 3651 3652 3653 3654 3655 3657 3658 3659 3660 3661 3662 3663 3664 3665 3666 3667 3668 3669 3671 3672 3673 3675 3676 3677 3679 3680 3681 3682 3683 3684 3685 3686 3687 3689 3690 3691 3693 3694 3695 369( 369f 369~ 370( C SERKH 186 0 SER H 186 N THR H 187- CA THR H 187 CB THR H 187 OGI THR H 187 CG2 THR H 187 C THRH 187- 0 THR H 187- N TRP H 188- CA TRP H 188 GB TRP H 188 CG TRP H 188 CD2 TRP H 188 CE2 TRP H 188 CE3 TRP H 188 CDI TRP H 188 NEI TRP H 188 CZ2 TRP H 188 CZ3 TRP H 188 CR2 TRP H 188 C TRP H 188 O TRP H 188 N PRO H 189 CID PRO H 189 CA PRO H 189 GB PRO H 189 CG PRO H 189 C PRO H 189 O PRO H 189 N SER H 190 CA SERKH 190 GB SER H 190 OG SER H 190 C SER H 190 O SER H 190 N GLU H 191 CA GLU H 191 GB GLU H 191 CG GLU H 191 CD GLU H 191 OEI GLU H 191 0E2 GLU H 191 C GLU H 191 0 GLUHI191 N THR H192 CA THR H 192 CGB THR H 192 OG I THR H 192 CG2 THR H 192 ~C THRHI192 0O THR H192 N VALHI193 C A VAL H 193 GB VAL H 193 CGI VAL H 193 13.358 1 14.198 12.808 -13 .302 -13.701 -12.531 14.724 12.278 12.507 11.142 -10. 135 -9.132 -8.154 -6.85 8 -6.335 -6.099 -8.344 -7.254 -5.091 -4.876 -4.3 77 1: 3.185 43.753 1.00 24.07 2.904 44.574 1.00 24.17 2.260 42.950 1.00 21.70 10.870 42.943 1.00 21.99 10.448 41.520 1.00 20.90 10.455 40.684 1.00 18.99 11.409 40.950 1.00 18.74 9.864 43.489 8.646 43.487 10.380 43.909 9.575 44.530 8.968 43.515 8.007 44.178 8.324 44.777 7.128 45.303 9.504 44.933 6.654 .44.375 6.147 45,044 7.07 1 45.959 9.447 45.589 8.233 46.092 1.00 23.01 1.00 23.61 1.00 20.48 1.00 21.24 1.00 15.29 1.00 11.67 1.00 8.04 1.00 8.99 1.00 8.90 1.00 13.61 1.00 14.95 1.00 12.53 1.00 10.52 1.00 12.29 392 10.463 45.500 1.00 20.69 -8.931 11.541 45.126 1.00 20.70 -9.147 -8.337 -9.526 -8.474 -8.368 .10.918 -11.094 .11.905 -13.246 -14.182 -1l4.42~ .13.818 -14.576 -13.5 10 -13.95 -14.74 -15.87 -16.92 -16.81 -17.8' -12.795 -1 1.64~ -13. 101 -1 2.08 -12.62 -13.0 -11.5 -11.55~ -12.314 -10.24 -9.59 -8.80 -7.9.

9.971 46.705 1.00 20.09 10.643 47.748 1.00 22.74 8.624 47.137 1.00 20.72 8.329 48.184 1.00 22.60 9.640 48.878 1.00 20.47 8.383 47.687 1.00 21.08 7.394 48.358 1.00 22.85 9.217 47.423 1.00 23.42 8.941 47.944 1.00 21.96 10.102 47.648 1.00 23.31 t 10.227 46.247 1.00 23.23 7.676 47.324 1.00 24.54 6.938 48.002 1.00 25.15 7.456 45.998 1.00 25.58 7 6.241 45.283 1.00 23.69 4 6.550 43.995 1.00 25.22 1 7.579 44.161 1.0028.53 .9 7.228 45.217 1.00 28.30 05 6.175 45.880 1.00 31.06 93 8.014 45.380 1.00 26.40 5.367 44.946 1.00 23.74 5.817 44.905 1.00 21.49 14.120 44.702 1.00 20.79 2 3.128 44.463 1.00 21.97 7 1.714 44.722 1.00 23.80 73 41 z 3 6 '1 41 11.631 46.085 1.00 29.80 0.666 44.485 1.00 27.22 3.164 43.062 1.00 18.87 3.259 42.102 1.00 15.94 3.098 42.963 1.00 16.81 2.918 41.685 1.00 16.97 4.205 41.206 1.00 16.54 3.913 39.955 1.00 11.61 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -266-

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3701 3702 3703 3704 3706 3707 3708 3710 3711 3712 3713 3715 3716 3717 3718 3719 3720 3722 3723 3724 3725 3726 3729 3730 3731 3733 3734 3735 3736 3737 3738 3739 3741 3742 3743 3744 3745 3747 3748 3749 3750 3751 3753 3754 3756 3757 3758 3759 3760 3761 3762 3763 3764 3765 3761 3761 GG2 VAL H 193 C VAL H 193 0 VALKH 193 N THR H 194 CA THR H 194 GB THR H 194 OG I THR H 194 GG2 THR H 194 C THR H 194 0 THR H 194 N CYS H 195 GA GYS H 195 GB3 GYS H 195 SG CYS H 195 C CYS H 195 O CYS H 195 N ASN H 196 GA ASN H 196 GB3 ASN H 196 CG ASN H 196 ODI ASN H 196 ND2 ASN H 196 C ASN H 196 0 ASN H 196 N VAL H 197 CA VAL H 197 GB VAL H 197 GI VAL H 197 GG2 VAL H 197 C VAL H 197 -9.8 18 5.3 19 40.874 1.00 14.87 -8.720 1.648 41.779 1.00 16.78 -7.864 1.514 42.626 1.00 14.37 -9.039 0.689 40.945 1.00 18.51 -8.348 -0.571 40.933 1.00 19.26 -9.335 -1.672 41.312 1.00 19.05 -10.070 -1.255 42.476 1.00 22.10 -8.625 -2.980 41.603 1.00 17.95 -7.871 -0.842 39.523 1.00 20.35 -8.575 -0.528 38.560 1.00 18.99 -6.683 -1.388 39.389 1.00 22.03 -6.241 -1.842 38.090 1.00 21.55 -4.838 -1.374 37.790 1.00 22.21 -3.531 -2.325 38.567 1.00 26.24 -6.320 -3.360 38.049 1.00 20.83 -6.051 -4.058 39.040 1.00 21.96 -6.712 -3.850 36.908 1.00 19.29 -6.924 -5.280 36.675 1.00 16.40 -8.297 -5.433 36.030 1.00 16.17 -9.253 -4.392 36.544 1.00 13.27 -9.664 -3.475 35.837 1.0020.19 -9.596 -4.5 10 37.798 1.00 11.17 -5.879 -5.762 35.690 1.00 16.19 -5,901 -5.343 34.545 1.00 13.42 -4.956 -6.602 36.133 1.00 15.57 -3.897 -7.065 35.269 1.00 14.42 -2.521 -6.834 35.890 1.00 9.60 -1.458 -7.389 34.966 1.00 7.11 -2.290 -5.354 36.125 1.00 12.01 -4.033 -8.547 34.954 1.00 16.35 -4.129 -9.376 35.874 1.00 14.56 -4.033 -8.874 33.646 1.00 17.13 -4.135 -10.267 33.214 1.00 16.34 -5.3 15 -10.444 32.302 1.00 17.48 -2.881 -10.680 32.503 1.00 18.98 -2.337 -9.926 31.692 1.00 18.73 -2.372 -11.845 32.860 1.00 18.76 VAL H 197 ALA H 198 ALA H 198 1 ALA H 198 ALA H 198 ALA H 198 HIS H 199 GA HIS H 199 GB HIS H 199 CG HIS H 199 GD2 HIS H 199 NDI HIS H 199 GEl HIS H 199 NE2 HIS H 199 G HIS H 199 O HIS H 199 N PRO H200 GD PRO H 200 GA PRO H200 GB PRO H200 GG PRO H 200 C PRO H200 0 PRO H200 N ALA H 201 CA ALA H 201 GB ALA H 201 -1.205 -12.400 -0.048 -12.500 1.206 -12.959 1.784 -12.605 2.076 -13.871 3.134 -14.074 2.957 -13.3 18 32.205 1.00 17.07 33.166 1.00 8.69 32.494 1.00 13.16 31.294 1.00 11.24 33.056 1.00 12.67 32.278 1.00 15.05 31.211 1.00 9.04 1.582 -13.790 31.698 1.00 20.77 1.357 -14.809 32.404 1.00 22.61 -2.203 -13.855 30.485 1.00 23.3 8 -2.513 -12.705 29.583 1.00 23.82 -2.640 -15.113 29.875 1.00 22.74 -2.769 -14.750 28.407 1.00 23.09 -3.303 -13.357 28.477 1.00 23.84 -1.671 -16.255 30.118 1.00 22.03 -2.091 -17.283 30.570 1.00 25.71 -0.382 -16.054 29.884 1.00 21.74 0.601 -17.137 30.024 1.00 22.02 1.987 -16.614 29.751 1.00 21.34 SUBSTITUTE SHEET (RULE WO 99/10379 WO 9910379PCT/GB98/02542 -267- ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM3 ATOM 3

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769 770 1771 773 1774 1775 1777 1778 1779 1781 1782 1783 5784 3785 3787 3788 3789 3791 3792 3793 3794 3796 3797 3798 3799 3800 3801 3805 3806 3807 3809 3810 3811 3812 3813 3814 3815 3817 3818 3819 3820 3821 3822 3823 3824 3826 3827 3828 3829 3830 3832 3833 3 834 3 835 383( 383',

C

c

C

c c ALA H 201 ALA H 201 SER H 202 SER H 202 ISER H202 3 SERH 202 SER H 202 SER H 202 ALA H 203 ALA H 203 1 ALA H 203 ALA H 203 ALA H 203 THR H 204 0.582 -17.840 3 1.399 1.00 25.49 0.590 -19.087 31.481 1.00 27.00 0.588 -17.055 32.476 1.00 23.97 0.534 -17.6 16 33.826 1.00 23.02 1.046 -16.570 34.790 1.00 20.89 0.321 -15.372 34.570 1.00 22.36 -0.908 -17.948 34.194 1.00 22.44 -1.196-18.417 35.282 1.00 24.26 -1.807 -17.686 33.281 1.00 23.52 -3.226 -17.820 33.547 1.00 24.82 -3.599 -19.299 33.632 1.00 25.98 -3.628 -17.046 34.835 1.00 28.71 -4.398 -17.533 35.678 1.00 33.42 -3.134 -15.820 34.995 1.00 27.17 -3.493 -15.056 36.184 1.00 27.24 -2.281 -14.722 37.006 1.00 26.73 -1.396-13.917 36.233 1.0029.32 -1.572-15.997 37.415 1.0030.85 -4.211 -13.756 35.845 1.0028.10 -4.034 -13.185 34.756 1.00 27.08 -5.018 -13.308 36.796 1.00 29.70 -5.805 -12.082 36.664 1.00 29.70 -7.176 -12.423 36.058 1.00 26.59 -8.106 -11.253 35.801 1.00 30.12

,A

'B

)G

-G

THR H 204 THR H 204 1 THR H 204 Z THR H 204 C THR H204 0 THRH 204 N LYSH 205 CA LYS H205 CB LYS H205 CG LYSH 205 CD LYS H205 CE LYSH 205 NZ LYS H 205 C LYSH 205 O LYSH 205 N VAL H206 CA VAL H 206 CB VAL H 206 CG I VAL H 206 CG2 VAL H 206 C VAL H206 0 VALH 206 N ASPH 207 CA ASP H 207 GB ASP H 207 CG ASP H 207 OD I ASP H207 0D2 ASP H 207 C ASPH 207 O ASPH 207 N ALAH 208 CA ALA H 208 GB ALA H 208 C ALAH 208 '0 ALA H208 N LYSH 209 CA LYSH 209 GB LYSH 209 CG LYS H 209 CD LYSH 209 CE LYS H209 NZ LYS H 209 -7.440 -10.121 -8.413 -8.995 -9.228 -9.292 -5.915 -11.443 -6.683 -11.903 -5.087 -10.414 35.041 34.687 33.456 38.056 38.906 38.287 1.00 32.29 1.00 28.46 1.00 32.30 1.00 29.50 1.00 29.82 1.00 27.91 -5.029 -9.767 39.575 1.00 27.55 -3.560 -9.755 40.139 1.00 27.51 -2.906 -11.112 39.930 1.00 29.90 -2.727 -8.654 39.511 1.00 25.31 -5.598 -8.334 39.578 1.00 26.86 -5.492 -7.595 38.607 1.00 25.39 -6.229 -7.982 40.70 1 1.00 27.63 -6.728 -6.638 40.940 1.00 25.50 -8.156 -6.677 41.442 1.00 28.55 -9.132 -6.941 40.337 1.00 29.54 -8.700 -6.972 39.168 1.00 36.07 -10.328 -7.118 40.628 1.00 32.67 -5.903 -5.997 42.008 1.00 24.44 -5.547 -6.682 42.978 1.00 23.66 -5.581 -4.706 41.827 1.00 21.43 -4.881 -3.943 42.848 1.00 17.91 -3.397 -3.781 42.534 1.00 20.11 -5.530 -2.574 43.035 1.00 16.62 -5.610 -1.753 42.086 1.00 10.62 -6.055 -2.358 44.261 1.00 16.90 -6.683 -1.079 44.621 1.00 15.48 -7.654 -1.222 45.812 1.00 10.13 -8.265 0.104 46.179 0.50 10.96 -9.145 -0.022 47.396 0.50 14.26 -9.497 1.346 47.938 0.50 12.83 -10.519 1.255 49.008 0.50 14.36 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -268- ATOM 2 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3

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841 842 843 845 846 1847 1848 1849 1850 1851 1852 1854 5855 3856 3857 3858 3859 3860 3861 3862 3863 3864 3865 3866 3867 3869 3870 3871 3872 3873 3875 3876 3879 3882 3883 3884 3885 3886 3887 3890 3892 3893 3895 3 896 3897 3 898 3 899 390( 3901 390~ 390: 390' 390: 3904 C LYSH 209 0 LYSH 209 N ILEH210 CA ILE H210 GB3 ILE H210 CG2 ILE H210 CG1 ILE H210 CD ILE H210 C ILEH-21O 0 ILEH210 N VALH 211 CA VAL H211 GB VAL H211 CG I VALH 211 CG2 VAL H 211 C VALH 211 0 VALH 211 N PROH 212 CD PRO H 212 CA PROH 212 GB PRO H 212 CG PROH 212 C PROH 212 O PROH 212 N ARGH 213 -5.627 -0.011 44.930 1.00 12.92 -4.648 -5.801 -4.850 -4.682 -3.43( -4.64: -3.468 -5.369 -6.5 14 -4.543 -4.83 -4.68 -4.8: -5.7' -0.268 45.6 16 1.00 10.83 1.183 44.380 1.00 12.54 2.250 44.663 1.00 14.57 3.263 43.473 1.00 10.03 4.074 43.671 1.00 9.58 2.540 42.097 1.00 11.38 1.613 41.881 1.00 9.16 2.976 45.910 1.00 16.98 3.474 45.936 1.00 18.38 2.941 46.931 1.00 19.13 1 3.528 48.240 1.00 20.34 8 2.416 49.299 1.00 21.28 37 2.986 50.708 1.00 25.89 05 1.316 49.035 1.00 18.88 ARG H 213 ARGH 213 ARG H 213 ARG H 213 ARG H 213 ARG H 213 -3.802 4.633 48.528 -2.617 4.473 48.212 -4.201 5.771 49.134 -5.573 6.115 49.582 -3.258 6.886 49.422 -4.145 7.920 50.099 -5.488 7.615 49.546 -2.124 6.456 50.338 -2.326 5.576 51.182 -0.926 7.043 50.151 0.187 6.766 51.05'- 1.569 6.813 50.343 1.860 7.978 49.39( 3.273 7.862 48.79] 3.507 6.520 48.24 4.615 5.771 48.49S 4.693 4.535 48.OC 5.649 6.260 49.2( 0.158 7.706 52.255 0.614 7.283 53.34 -0.357 8.840 52.1C 1.00 19.87 1.00 20.58 1.00 21.21 1.00 18.81 1.00 20.72 1.00 18.51 1.00 18.18 1.00 23.63 1.00 27.07 1.00 24.57 1 1.00 26.72 1.00 27.15 i1.00 33.85 1 1.0033.12 11.00 40.88 I1.00 40.65 11 1.00 39.58 16 1.00 37.54 1.00 27.92 1 1.00 31.74 )9 1.00 29.09 5 5 NHI ARG H 212 NH2 ARGH 213 C ARG H213 OTI ARG H 213 On2 ARG H 212 C13ALA P 2 C ALA P 2 0 ALA P 2 N ALA P 2 CA ALA P 2 N ALA P 3 CA ALA P 3 CB3 ALA P 3 C ALA P 3 O ALA P 3 N PRO P 4 CD PROP 4 CA PROP 4 C1B PROP 4 CG PROP 4 C PROP 4 O PROP 4 N ASP P 5 CA ASP P 5 CB ASP P 5 3 1.237 -7.993 -6.254 1.00 23.82 29.863 -5.868 -6.170 1.00 18.78 29.809 -5.461 -5.015 1.00 18.94 32.338 -5.778 -6.117 1.00 24.56 3 1.159 -6.526 -6.677 1.00 20.94 28.844 -5.788 -7.037 1.00 15.73 27.600 -5.082 -6.736 1.00 14.42 27.064 -4.460 -8.021 1.00 13.90 26.498 -5.955 -6.132 1.00 14.34 26.523 -7.202 -6.212 1.00 12.83 25.53 1 -5.280 -5.47 1 1.00 12.41 25.569 -3.841 -5.120 1.00 10.70 24.365 -5.915 -4.878 1.00 9.09 23.912 -4.871 -3.871 1.00 10.23 24.158 -3.624 -4.622 1.00 10.28 23.350 -6.158 -5.998 1.00 8.50 23.720 -6.084 -7.147 1.00 12.29 22.110 -6.436 -5.707 1.00 3.44 21.187 -6.699 -6.748 1.00 6.24 19.976 -7.498 -6.231 1.00 4.87 SUBSTITUTE SHEET (RULE ATOM 3908 ATOM 3909 WO 99/10379 WO 9910379PCT/GB98/02542 -269- ATOM 2 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM 3 ATOM3 ATOM3

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910 911 912 913 914 1915 1917 1918 1919 1921 1922 1923 1924 3926 3927 3928 3929 3930 3932 3933 3936 3939 3940 3941 3942 3943 3944 3945 3946 3947 3948 3950 3951 3952 3953 3954 3955 3956 3957~ 3958 3959 3960 3961 396', 3961 3962 397.

397~ 397.

3984 398 398 398 399 399 399 GG ASPP 5 OD1 ASP P 5 OD2 ASP P 5 C ASP P 5 0 ASP P 5 N THR P 6 GA THR P 6 GB THR P 6 OGI THR P 6 GG2 THR P 6 C THRP 6 0 THR P 6 N ARG P 7 GA ARG P 7 GB ARG P 7 CG ARG P 7 CD ARG P 7 NE AROP 7 CZ ARGP 7 NH1 ARG P 7 NH2 ARG P 7 C ARG P 7 0 ARG P 7 N PROP 8 GD PRO P 8 CA PRO P 8 GB PROP 8 GG PROP 8 C PROP 8 O PROP 8 N ALA P 9 GA ALA P 9 GB ALA P 9 G ALA P 9 O ALA P 9 N PROP 10 GD PROP 10 GA PRO P 10 GB PROP 10 G PRO P 10 G PRO P 10 OTI PROP I 072 PROP I OH2 WAT W OH2 WAT W 8 OH2 WAT W I OH2 WAT W 4 OH2 WAT W 7 OH2 WAT W 0i 0H2 WAT W 3 OH2 WAT W 6 OH2 WAT W 9 OH2 WAT W 2 OH-2 WAT W 5 OH2 WAT W 8 OH2 WAT W 18.947 -7.830 -7.322 1.00 8.73 19.286 -7.812 -8.552 1.00 5.17 17.787 -8.099 -6.971 1.00 6.00 20.734 -5.385 -7.386 1.00 11 .49 19.876 -4.707 -6.867 1.00 13.66 21.3 10 -5.045 -8.542 1.00 13.74 20.984 -3.797 -9.202 1.00 13.90 22.263 -3.137 -9.774 1.00 13.32 22.896 -4.001 -10.73 1 1.00 19.82 23.263 -2.884 -8.651 1.00 17.80 19.944 -3.952 -10.296 1.00 13.91 19.789 -3.050 -11.122 1.00 16.59 19.213 -5.065 -10.338 1.00 12.22 18.204 -5.190 -11.372 1.00 12.33 17.679 -6.625 -11.529 1.00 11.79 16.4 16 -6.694 -12.378 1.00 14.75 15.741 -8.045 -12.383 1.00 18.52 16.521 -8.985 -13.132 1.0027.19 16.062 -9.667 -14.164 1.00 26.31 16.877 -10.489 -14.780 1.00 31.37 14.807 -9.547 -14.576 1.00 25.93 17.054 -4.242 -11.085 1.00 15.83 16.730 -3.991 -9.908 1.00 15.84 16.445 -3.636 -12.151 1.00 15.86 16.848 -3.723 -13.596 1.00 15.67 15.332 -2.725 -11.993 1.00 11.60 15.082 -2.163 -13.418 1.00 16.26 16.398 -2.372 -14.113 1.00 12.50 14.099 -3.443 -11.426 1.00 15.08 13.731 -4.578 -11.824 1.00 7.39 13.513 -2.754 -10.452 1.00 14.65 12.318 -3.174 -9.766 1.00 16.28 12.035 -2.141 -8.639 1.00 13.79 11.143 -3.185 -10.727 1.00 17.17 11.197 -2.526 -11.760 1.00 19.75 10.136 -4.011 -10.481 1.00 17.47 10.149 -5.176 -9.580 1.00 17.04 8.950 -3.999 -11.292 1.0020.33 4 8.088 -5.104 -10.680 1.00 14.66 8.708 -5.384 -9.367 1.00 18.16 8.280 -2.585 -11.246 1.00 23.98 0 8.663 -1.761 -10.374 1.00 29.12 0 7.407 -2.300 -12.100 1.00 32.81 1 6.469 14.788 -4.498 1.00 14.28 2 17.598-23.808 -4.151 1.00 21.81 3 18.632 4.032 58.157 1.00 6.32 4 25.496 3.194 -6.045 1.00 13.58 5 16.953 -5.194 -7.526 1.00 13.00 6 24.903 -22.960 6.237 1.00 30.37 7 21.593 -21.679 -1.338 1.00 3.40 8 -3.000 -3.337 28.274 1.00 30.92 9 29.010 -11.559 3.896 1.00 9.44 10 -2.022 11.290 49.065 1.00 32.00 11 8.407 -21-513 8.625 1.00 13.78 12 13.728 27.079 30.459 1.00 39.32 13 3.495 4.636 44.813 1.00 13.19 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -270- ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4 ATOM 4

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001 004 007 010 013 016 019 022 025 028 1031 034 037 5040 5043 1046 049 1052 055 1058 1061 t064 t067 4070 1073 1076 4079 4082 4085 4088 4091 4094 4097 4100 4103 4106 4109 4112 4115 4118 4121 412z 412' 413( 413: 413< 413 414: 414 414 415 415 415 416 416 416 OH2WATW 14 OH2WATW 15 OH2WATW 16 OH2WATW 17 OH2WATW 18 OH2WATW 19 OH2 WAT W 20 OH2WATW 21 OH2 WAT W 22 OH2 WAT W 23 OH2 WAT W 24 OH2 WAT W 25 OH2 WAT W 26 OH2 WAT W 27 OH2 WAT W 28 OH2 WAT W 29 OH2 WAT W 30 OH2WATW 31 OH2 WAT W 32 OH2 WAT W 33 OH2 WAT W 34 OH2 WAT W 35 OH2 WAT W 36 OH2 WAT W 37 OH2 WAT W 38 OH2 WAT W 39 OH2 WAT W 40 OH2WATW 41 OH2 WAT W 42 OH2 WAT W 43 OH2 WAT W 44 OH2 WAT W 45 OH2 WAT W 46 OH2 WAT W 47 OH2 WAT W 48 OH2 WAT W 49 OH2WATW 50 OH2 WATW 51 OH2 WAT W 52 OH2 WAT W 53 OH2 WAT W 54 SOH2WATW 55 1 O0H2WATW 56 OH2WATW 57 3 OH2WATW 58 6 OH2WATW 59 9 OH2WATW 60 2 OH2WATW 61 5 OH2WATW 62 8 OH2 WAT W 63 1 OH2WATW 64 4 0H2 WAT W 65 7 OH2 WAT W 66 0 OH2 WAT W 67 3 OH2 WATW 68 6 OH2 WAT W 69 1.218 15.946 14.314 1.0022.53 12.903-17.138 34.597 1.00 19.15 10.898 -8.237 -12.633 8.064-14.542 21.148 21.359 7.434 14.511 -1.648 1.908 47.014 16.737 9.406 27.272 20.693 12.449 -7.122 7.885-12.508 25.316 -3.655 16.264 24.900 33.177 3.183 45.356 -11.952 -7.879 37.114 25.803 12.531 -5.964 -2.656 4.045 26.085 7.532 17.937 41.724 1.0021.26 1.0037.92 1.00 18.86 1.00 15.06 1.00 14.21 1.00 16.36 1.00 10.64 1.0033.41 1.00 8.24 1.0026.57 1.0021.74 1.00 17.07 1.0022.01 23.879 -14.777 31.338 -2.334 17.502 7.886 5.941 -12.525 5.404 -1.056 11.009-16.411 6.478 -14.860 24.976 1.00 8.54 -1.810 1.00 19.31 16.158 1.0028.03 39.932 1.0020.30 17.882 1.0034.15 36.548 1.00 16.42 -8.201 1.00 16.12 9.172 0.986 -2.279 1.0022.74 4.511 -4.656 10.403 1.0020.60 20.413 -25.507 7.710 -2.607 21.067 -25.174 14.047 -12.643 24.985 -8.571 18.061 -3.176 8.725 -22.350 12.305 -7.538 3.222 -16.789 7.708 1.725 -8.378 28.83 16.098 49.972 12.897 37.86( -4.360 1.0026.25 1.00 13.86 1.00 17.33 1 1.00 15.39 1.00 16.92 1.00 25.44 1.00 22.95 1.00 26.88 S1.00 19.56 1.00 30.33 S1.00 5.88 1 1.00 15.25 1.00 12.48 4 1.0026.95 6 1.0021.65 :1 1.00 19.62 0.557 0,177 50.267 19.082-24.999 2.779 19.857 5.737-10.59 27.548-18.756 1.69( 18.386 -0.621 -10.50 14.332-24.453 3.09 15.420-11.836 25.52 7.048 -3.604 7.452 1.00 10.22 8.771 -20.550 29.022 1.0024.86 7.223 14.260. 47.625 1.00 38.64 28.000-19.890 -6.750 1.00 5.62 25.854-19.568 7.742 1.00 10.53 21.053-23.375-10.438 1.00 13.82 27.634 -1.672 12.546 1.0016.07 4.320-13.192 12.140 1.0029.58 10.805-25.481 15.446 1.0030.70 16.133 5.455 14.708 1.0033.54 18.557 -2.351 28.596 1.0029.04 11.919 1.172 24.227 1.0027.66 20.602 0.152 12.952 1.0013.20 2.523 2.197 48.994 1.0025.99 18.370 -9.737 -9.821 1.00 8.99 12.339 -2.363 38.736 1.00 18.95 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -271-

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4169 4172 4175 4178 4181 4184 4187 4190 4193 4196 4199 4202 4205 4208 4211 4214 4217 4220 4223 4226 4229 4232 4235 4238 4241 4244 4247 4250 4253 4256 4259 4262 4265 4268 4271 4274 4277 4280 4283 4286 4289 4292 4295 4298 4301 4304 4307 4310 4313 4316 4319 4322 4325 4328 4331 4334 OH2 WAT W 70 OH2WATW 71 OH2 WAT W 72 OH2 WAT W 73 OH2 WAT W 74 OH2 WAT W 75 OH2 WAT W 76 OH2 WAT W 77 OH2 WAT W 78 OH2 WAT W 79 OH2 WAT W 80 OH2WATW 81 OH2 WAT W 82 OH2 WAT W 83 OH2 WAT W 84 OH2 WAT W 85 OH2 WAT W 86 OH2WATW 87 OH2 WAT W 88 OH2 WAT W 89 OH2 WAT W 90 OH2WATW 91 OH2 WAT W 92 OH2 WAT W 93 OH2WATW 94 OH2 WAT W 95 OH2 WAT W 96 OH2 WAT W 97 OH2 WAT W 98 OH2WATW 99 OH2 WAT W 100 OH2WATW 101 OH2 WAT W 102 OH2WATW 103 OH2 WATW 104 OH2 WATW 105 OH2WATW 106 OH2 WAT W 107 OH2WATW 108 OH2 WAT W 109 OH2 WAT W 110 OH2 WAT W 111I OH2WATW 112 OH2WATW 113 OH2WATW 114 OH2 WAT W 115 OH2WATW 116 OH2 WAT W 117 OH2 WAT W 118 OH2 WAT W 119 OH2 WAT W 120 OH2WATW 121 OH2 WAT W 122 OH2 WAT W 123 OH2 WAT W 124 OH2WATW 125 28.531 -9.198 -6.241 1.00 15.87 7.113 2.252 42.134 1.0024.77 5.551 -6.218 1.097 1.0025.37 27.031 -2.271 -10.652 1.00 35.24 23.700 -4.680 9.160 1.00 10.39 21.927 -8.069-10.281 1.0019.23 9.255 21.329 27.676 1.0022.97 -1.050 9.080 47.795 1.00 17.17 23.569 -2.863 10.958 1.00 11.39 14.936-18.091 -13.265 1.00 38.75 18.885 -22.021 -1.608 1.0016.43 6.214 9.528 3.424 1.00 10.35 8.852 -8.980 40.128 1.00 19.41 13.989 26.590 5.643 1.0030.50 14.832 15.962 -3.151 1.0014.73 22.345 -12.016 -10.082 1.00 12.02 11.978-24.989 2.736 1.00 17.04 14.518-25.660 19.374 1.00 12.97 26.181 0.882 12.155 1.0014.84 3.965 18.045 34.071 1.00 14.92 2.944-12.722 -0.100 1.0030.35 21.018 -0.090 -7.931 1.0011.45 17.704 4.172 55.338 1.0023.03 30.887-19.001 0.180 1.0018.12 8.090 0.598-12.040 1.0035.87 -0.137 11.808 40.511 1.0019.09 25.436 11.667 49.096 1.00 39.93 13.418 9.927 61.190 1.0017.48 31.648 7.847 -5.602 1.0019.58 15.243 0.341 35.899 1.0011.83 -5.216-15.339 38.926 1.00 16.58 1.803 -1.527 48.192 1.0029.29 -9.962 4.701 47.615 1.0027.17 6.926 1.104 30.511 1.0021.69 20.040 0.675 43.899 1.00 28.97 6.476 6.252 15.949 1.0021.65 13.134 23.738 -4.232 1.00 9.47 -9.097 -5.473 44.708 1.0032.78 29.597-16.402 0.794 1.0023.02 1.393 12.084 -0.555 1.0027.33 32.275 10.498 -1.711 1.0022.13 28.840 -8.588 8.722 1.0016.73 24.301 5.966-10.135 1.0017.97 13.047-12.047 26.295 1.00 17.02 23.665-12.540 16.941 1.00 18.85 28.346 2.252-10.297 1.0057.76 16.579-26.334 6.701 1.0014.43 25.807 11.294 9.613 1.0020.54 32.494 10.036 -4.577 1.0028.60 32.460 4.112 -6.893 1.0045.04 -11.721 12.136 46.764 1.0024.53 2.092-13.612 -7.710 1.0034.84 5.719 -8.608 46.184 1.0013.18 15.576 -9.029 24.115 1.0030.63 27.668-17.190 14.414 1.00 14.55 -17.404 6.631 48.404 1.0017.20 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -272-

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1337 4340 1343 1346 1349 1352 1355 1358 1361 1364 1367 1370 4373 4376 4379 4382 4385 4388 4391 4394 4397 4400 4403 4406 4409 4412 4415 4418 4421 4424 4427 4430 4433 4436 4439 4442 4445 4448 4451 4454 4457 4460 4463 4466 4469 4472 4475 4478 4481 4484 4487 449( 4493 449( 449 450 OH2 WAT W 126 OH2 WAT W 127 OH2 WAT W 128 OH2 WAT W 129 OH2WATW 130 OH2WATW 131 OH2 WAT W 132 OH2 WAT W 133 OH2 WAT W 134 OH2 WAT W 135 OH2 WAT W 136 OH2WATW 137 OH2 WAT W 138 OH2 WAT W 139 OH2 WAT W 140 OH2WATW 141 OH2 WAT W 142 OH2 WAT W 143 OH2 WAT W 144 OH2WATW 145 OH2 WAT W 146 OH2WATW 147 OH2 WAT W 148 OH2 WAT W 149 OH2 WAT W 150 OH2WATW 151 OH2 WAT W 152 OH2 WAT W 153 OH2 WAT W 154 OH2WATW 155 OH2 WAT W 156 OH2 WATW 157 OH2WATW 158 OH2 WAT W 159 OH2 WAT W 160 OH2WATW 161 OH2 WAT W 162 OH2 WAT W 163 OH2 WAT W 164 OH2WATW 165 OH2 WAT W 166 OH2 WATW 167 OH2 WAT W 168 OH2WATW 169 SOH2WATW 170 SOH2WATW 171 OH2WATW 172 OH2WATW 173 OH2 WATW 174 I OH2 WAT W 175 OH2WATW 176 SOH2WATW 177 SOH2WATW 178 5 OH2WATW 179 OH2WATW 180 Z OH2WATW 181 23.431 -13.579 22.761 1.00 26.67 17.744 14.051 -9.668 5.213 31.931 14.297 34.060 1.470 5.680 0.532 -6.655 8.541 -2.797 -3.373 26.979 1.00 47.02 21.680 1.00 23.91 31.275 1.00 16.36 -15.383 1.0038.16 5.215 1.00 13.75 27.765 1.00 27.48 1.190 1.0028.35 -11.712 1.0016.01 7 25.495 1.00 21.80 2.261 1.00 18.43 8.266 -8.418 21.210 -24.74 38.415 7.827 7.104 11.613 49.567 1.00 16.91 22.354 8.172 -1.094 1.00 3.60 -0.649 13.876 3.532 20.509 26.020 -21.708 16.768 19.739 22.933 1.122 13.952-25.966 -1.798-13.563 31.947 -3.239 -4.303 -0.614 38.964 1.0053.27 33.354 1.0025.23 3.681 1.00 8.89 12.715 1.00 12.58 -9.255 1.0033.61 12.995 1.00 18.24 5.388 1.0022.46 6.296 1.0021.74 28.886 1.0026.69 21.134-26.915 23.907 1.00 16.34 21.965 7.892-11.778 1.0026.06 10.626-24.261 12.603 1.0021.28 4.596 13.855 -6.210 1.00 7.70 30.277 6.152 11.049 1.0016.94 24.985 -7.067 9.817 1.00 17.58 11.329 -3.862 36.792 1.00 23.50 -15.325 3.494 41.706 1.0035.32 15.210-24.587 -4.662 1.0018.53 1.420 -5.547 7.576 1.00 23.51 -11.870 17.085 41.012 1.0030.42 6.864-18.801 12.992 -0.675 33.462 -5.652 13.931 24.641 1.149-14.946 24.449 -8.330 3.122 11.598 28.608 26.187 6.209 31.377 26.149 -9.652 42.075 1.00 19.33 1.0021.36 1.0023.60 1.0036.78 1.0029.62 1.00 15.70 1.0020.46 1.0013.45 1.0031.64 1.0032.66 10.713 22.846 -4.457 -6.701 -5.190 46.412 5.589 -4.185 17.993 -20.269 5.845 18.348 -6.708 29.246 -15.130 15.259 12.226 17.143-24.993 8.818 -1.363 1 32.233 -8.889 28.467 -17.015 6.024 25.034 20.243 3.145 -0.519-13.612 34.547 -2.642 15.392 2.520 3.788 54.789 -9.493 9.163 4.729 -2.185 11.136 40.487 40.661 5.862 1.00 11.80 1.00 3.86 1.0014.16 1.0037.54 1.0035.04 1.0036.48 1.00 19.69 1.00 5.68 1.0022.81 1.0023.82 1.0030.50 1.0021.60 7.161 4.607 25.463 1.0015.09 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -273-

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4505 4508 4511 4514 4517 4520 4523 4526 4529 4532 4535 4538 4541 4544 4547 4550 4553 4556 4559 4562 4565 4568 4571 4574 4577 4580 4583 4586 4589 4592 4595 4598 4601 4604 4607 4610 4613 4616 4619 4622 4625 4628 4631 4634 4637 464C 4643 4646 4649 4652 4655 4651 466 466' 466' 467C OH2 WAT W 182 OH2 WATW 183 OH2 WAT W 184 OH2 WAT W 185 OH2 WAT W 186 OH2 WAT W 187 OH2 WAT W 188 OH2 WAT W 189 OH2 WAT W 190 OH2WATW 191 OH2 WAT W 192 OH2 WAT W 193 OH2 WAT W 194 OH2 WAT W 195 OH2 WAT W 196 OH2 WATW 197 OH2 WAT W 198 OH2 WAT W 199 OH2 WAT W 200 OH2 WAT W 201 OH2 WAT W 202 OH2 WAT W 203 OH2 WAT W 204 OH2 WAT W 205 OH2 WAT W 206 OH2 WAT W 207 OH2 WAT W 208 OH2 WAT W 209 OH2 WAT W 210 OH2 WATW 211 OH2WATW 212 OH2 WAT W 213 OH2WATW 214 OH2 WAT W 215 OH2 WAT W 216 OH2 WAT W 217 OH2 WAT W 218 OH2 WAT W 219 OH2 WAT W 220 OH2 WAT W 221 OH2 WAT W 222 OH2 WAT W 223 OH2 WAT W 224 OH2 WAT W 225 OH2 WAT W 226 OH2 WAT W 227 OH2WATW 228 OH2 WAT W 229 OH2WATW 230 OH2WATW 231 OH2WATW 232 8 OH2WATW 233 1 OH2 WAT W 234 4 OH2 WAT W 235 7 OH2 WAT W 236 3 OH2 WAT W 237 -4.704 11.611 31.080 1.0020.86 21.433-23.454 9.547 1.0031.82 13.857 17.680 46.003 1.0021.96 17.187-16.883-12.460 1.0020.68 19.746-21.300-14.638 1.0027.48 12.148 14.642 15.368 1.00 19.96 5.387 -6.500-12.696 1.00 35.66 4.586 13.697 39.870 1.0020.33 21.769 5.215 41.762 1.0036.13 29.219-21.787 7.401 1.0020.15 17.974 12.473 13.012 25.597 24.837 27.972 26.863 15.918 5.655 23.425 4.290 0.290 25.007 20.205 -3.217 -9.978 24.596 1.0036.15 -28.071 4.359 1.00 18.19 10.112 21.862 1.0038.97 8.673 49.783 1.0027.52 10.769 46.030 1.00 10.14 -17.140 -7.933 1.0047.72 3.704 48.558 1.0027.25 0.432 -1.511 1.00 13.61 -3.768 25.280 1.0030.04 6.240 13.624 1.00 11.98 5.208 17.451 1.0021.77 -9.212 42.200 1.00 15.59 2.912 -8.754 1.00 19.57 1.110 -9.843 1.0034.32 8.862 32.830 1.00 6.08 16.144-17.034 -8.816 1.00 22.31 19.175 8.807-10.884 1.0042.96 1.655 -6.944 45.357 1.0037.43 -8.549 4.472 49.787 1.0025.82 3.867 -7.430 27.878 1.0027.19 23.654 -2.619-13.589 1.00 28.44 29.110 12.286 -6.363 1.0038.04 23.926-20.838 2.405 1.00 5.04 27.197 3.738 37.195 1.0024.05 5.195-12.115 14.877 1.00 13.79 7.487 4.063 14.308 1.0026.14 20.375 10.379 8.335 1.00 2.00 17.302 -1.823 -8.469 1.00 18.45 6.804 18.384 -1.961 1.00 18.17 30.521 -17.401 -8.988 1.00 9.31 1.118-13.903 28.627 1.0022.20 4.658 4.612 24.950 1.0014.99 0.009 17.440 18.293 1.0024.15 9.924 -27.510 -4.500 1.0024.23 17.922 7.851 29.078 1.0026.71 26.329 5.158 -2.190 1.00 7.58 16.212 -0.659 25.988 1.00 51.29 8.255-11.625 39.145 1.0024.13 -0.739 11.893 32.356 1.0014.96 10.244 -6.616 43.601 1.0027.57 0.924 9.055 32.613 1.0024.54 2.598 11.742 32.894 1.00 21.65 6.719 -0.044 43.519 1.0010.20 18.217-24.604 5.251 1.00 11.95 8.252 6.201 12.463 1.0021.41 23.441 13.635 49.710 1.00 30.08 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -274- ATOM 4 ATOM 4 ATOM 4

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1673 1676 1679 1682 1685 4688 1691 1694 t697 1700 1703 1706 1709 1712 4715 4718 4721 4724 4727 4730 4733 4736 4739 4742 4745 4748 4751 4754 4757 4760 4763 4766 4769 4772 4775 4778 4781 4784 4787 4790 4793 4796 4799 4802 4805 4801 481 481- 481' 482 482: 482' 482 483 483 483 OH2 WAT W 238 OH2 WAT W 239 OH2 WAT W 240 OH2 WAT W 241 OH2 WAT W 242 OH2 WAT W 243 OH2 WAT W 244 OH2 WAT W 245 OH2 WAT W 246 OH2 WAT W 247 OH2 WAT W 248 OH2 WAT W 249 OH2 WAT W 250 OH2 WAT W 251 OH2 WAT W 252 OH2 WAT W 253 OH2 WAT W 254 OH2 WAT W 255 OH2 WAT W 256 OH2 WAT W 257 OH2 WAT W 258 OH2 WAT W 259 OH2 WAT W 260 OH2 WAT W 261 OH2 WAT W 262 OH2 WAT W 263 OH2 WAT W 264 OH2 WAT W 265 OH2 WAT W 266 OH2 WAT W 267 OH2 WAT W 268 OH2 WAT W 269 OH2 WAT W 270 OH2 WAT W 271 OH2 WAT W 272 OH2 WAT W 273 OH2 WAT W 274 OH2 WAT W 275 OH2 WAT W 276 I OH2 WAT W 277 OH2 WAT W 278 OH2 WAT W 279 OH2 WAT W 280 SOH2 WAT W 281 5 OH2 WAT W 282 8 OH2 WAT W 283 I OH2 WAT W 284 4 OH2 WAT W 285 7 OH2 WAT W 286 0 OH2 WAT W 287 3 OH2 WAT W 288 6 OH2 WAT W 289 9 OH2 WAT W 290 2 OH2 WAT W 291 5 OH2 WAT W 292 8 OH2 WAT W 293 17.020 -7.750 -4.400 1.00 15.78 30.779-10.002 6.550 1.00 27.21 -6.748 -6.499 3 16.503 -12.922 12.122 -24.490 21.099 12.849 18.243 -8.436 20.147 10.002 29.723 9.471 13.252 2.121 23.464 -25.374 14.000 -22.772 10.326 0.557 13.521 2.393 13.615 -26.397 24.833 10.111 13.064 -15.952 12.312 1.0029.81 28.084 -7.899 35.212 20.387 34.434 -8.340 14.964 4.258 -6.620 16.215 -9.514 -3.875 -7.130 -13.595 39.924 31.027 43.712 23.940 1.0036.06 1.00 19.39 1.0024.60 1.0023.62 1.00 11.86 1.0034.43 1.0024.74 1.00 13.44 1.00 17.30 1.0041.70 1.0020.28 1.00 15.20 1.0029.35 1.0026.25 1.0039.38 1.00 19.01 1.0020.05 1.0041.00 -15.057 16.336 12.624 12.967 14.757 19.819 5.686 15.971 -9.192 -8.262 0.585 -10.768 1.00 28.58 -1.817-13.475 1.00 35.11 31.389 -15.656 -0.825 1.00 26.24 14.395-13.087-16.099 1.00 16.37 22.719 13.037 16.198 1.0021.47 16.540 21.557 39.053 1.00 26.03 -6.562 -9.693 42.850 1.0026.79 32.765 6.771 -7.894 1.0026.76 7.895 14.072 16.472 1.00 18.53 35.614 1.144 10.445 1.0031.99 13.248 -7.824 41.224 1.0027.81 26.612 -16.221 -10.354 1.00 24.35 9.404 21.743 36.231 1.0026.21 2.135 -1.886 26.621 1.00 19.18 5.029-16.489 24.250 1.00 21.38 -3.689 11.484 26.196 1.0032.16 -0.444 20.210 19.609 1.0028.61 20.202 13.824 -1.393 1.00 6.13 8.008 8.335 14.152 1.0026.36 -0.089 -4.167 27.283 1.0022.58 6.446-12.379 22.877 1.00 39.32 27.976 -9.405 11.870 1.0021.31 18.063 -5.600 47.215 1.0028.13 27.726-20.314 5.883 1.0029.05 7.306 3.337 5.457 1.00 15.35 -1.946 14.609 1.577 1.0030.36 11.677 -3.115 17.818 1.00 19.72 21.862-21.678 1.194 1.0014.10 21.062 -6.560 -2.887 1.00 10.76 15.270 0.156 17.566 1.0023.02 17.300 -6.730 54.194 1.0023.81 22.196-16.787 24.840 1.0026.10 11.450 -1.461 -14.210 1.0017.37 9.545 1.106 23.451 1.00 18.75 13.359 17.520 21.914 1.0032.59 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -275-

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4841 4844 4847 4850 4853 4856 4859 4862 4865 4868 4871 4874 4877 4880 4883 4886 4889 4892 4895 4898 4901 4904 4907 4910 4913 4916 4919 4922 4925 4928 4931 4934 4937 4940 4943 4946 4949 4952 OH2 WAT W 294 OH2 WAT W 295 OH2 WAT W 296 OH2 WAT W 297 OH2 WAT W 298 OH2 WAT W 299 OH2 WAT W 300 OH2 WAT W 301 OH2 WAT W 302 OH2 WAT W 303 OH2 WAT W 304 OH2 WAT W 305 OH2 WAT W 306 OH2 WAT W 307 OH2 WAT W 308 OH2 WAT W 309 OH2 WAT W 310 OH2 WAT W 311 OH2 WAT W 312 OH2 WAT W 313 OH2 WAT W 314 OH2 WAT W 315 OH2 WAT W 31 OH2 WAT W 31 OH2 WAT W 318 OH2 WAT W 319 OH2 WAT W 32( OH2 WAT W 32 OH2 WAT W 32: OH2 WAT W 32: OH2 WAT W 324 OH2 WAT W 32.

OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 32 OH2 WAT W 33 OH2 WAT W 33 26.885 -7.151 7.996 1.00 19.34 21.756 -13.103 -13.701 1.00 29.49 11.457 -7.218 35.141 1.0022.34 18.708 0.544 -7.701 1.00 16.39 -15.953 3.350 44.816 1.00 37.24 8.407 -8.314 42.681 1.0028.38 2.540 -9.294 23.041 1.0035.16 22.018 -7.958 -0.799 1.00 6.11 21.966 -24.488 2.085 1.00 8.66 20.076-25.315 17.635 1.00 9.01 17.006 -22.056 5.026 1.00 5.97 6.060 -7.502 14.185 1.0041.33 32.819 -13.271 -1.536 1.00 7.51 -7.134 13.283 28.131 1.00 26.60 6.093 -19.675 20.689 1.00 34.63 5.245 8.997 12.387 1.00 19.78 12.019 2.613 52.929 1.0021.69 10.010 19.928 41.543 1.00 33.05 13.142 -23.671 -10.200 1.00 36.76 8.670 -24.177 7.948 1.0034.91 29.062 -9.848 -3.498 1.00 29.41 14.807 -9.227 46.355 1.00 40.86 5 7.251 26.098 3.963 1.0028.36 7 23.961 5.881 39.286 1.00 21.45 8 8.771 7.324 16.718 1.0036.71 9 -1.090 -7.807 23.575 1.00 40.27 0 22.689 2.991 44.255 1.0031.90 1 11.210 -9.771 22.151 1.00 38.45 2 22.311 0.357 -12.113 1.0023.98 3 6.735 14.216 -9.674 1.0045.55 4 -8.071 -4.209 27.927 1.00 29.83 5 1.445 17.951 34.713 1.0030.61 6 19.684 9.965 25.552 1.00 33.30 7 2.120 14.444 12.302 1.0037.11 8 15.167 -4.201 25.183 1.00 29.17 9 12.976 28.071 24.361 1.00 30.90 0 1.965 -6.101 27.052 1.00 18.90 1 20.107 17.468 33.762 1.00 41.90 -3.687 11.892 28.658 1.00 34.52 7.014 -2.547 18.557 1.0056.55 -18.910 6.317 46.958 1.0025.08 31.181 -13.966 -2.383 1.00 17.70 7.075 -7.626-14.342 1.00 57.21 9.353 21.680 25.019 0.75 48.85 22.069 5.816 -10.264 0.75 26.79 17.818 -0.561 27.627 0.75 56.40 -19.039 3.937 48.052 1.0022.14 30.927 -12.252 -4.117 1.00 26.88 4955 CD 4956 CD 4957 CD 4958 CD 4959 CD 4960 CD 4961 CD 4962 CD 4963 CL 4964 CL HET I HET I HET I HET I HET I HET I HET I HET I CHL I CHL I SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -276- Table 3 Data statistics of SM3 Fab fragment/MUC1 epitope crystal D(A) No. of Completeness Multiplicity Average observed of data I/o(I) reflections in shell 6.06 1125 96.2 3.5 15.7 4.33 1994 98.8 3.6 14.7 3.54 2428 96.1 3.4 13.1 3.07 2985 98.1 3.5 10.8 2.75 3374 98.0 3.5 10.9 2.51 3718 98.0 3.5 2.33 3965 96.3 3.4 2.18 4299 97.3 3.1 3.4 2.06 4528 96.4 3.3 3.6 1.95 4623 93.2 3.2 3.1 Total 33093 96.6 3.4 8.1 D is the resolution defined as the interplanar spacings d=lambda/2 sintheta corresponding to the maximum observed 2theta values where lambda=1.54 angstroms. 2theta refers to the angle of diffraction. Lower resolutions have.

higher nos and higher resolutions have lower nos.

.I=intensity and sig(i) gives the standard deviation of the intensity for each batch of reflections. This indicates how well measured the data is. Higher values means stronger more intense data lower values mean the data is weakly measured. Note this value drops off as the resolution becomes higher, for example at 1.95 A the angle of diffraction is quite great.

SUBSTITUTE SHEET(RULE 26) WO 99/10379 PCT/GB98/02542 -277- Table 4 Summary of the refinement statistics for the SM3-EP1 structure.

Statistics for Table 2a Resolution range 8.0 1.95 A No. of residues 434 Missing residues 16 No. of protein atoms 3193 No. of solvent atoms 335 No. of metal atoms 8 No. of reflections with I 2.5 o(I) (all data) 32197 (27688) Space group P 2, Cell dimensions a=42.2; b=83.7; c=67.2 A, P= 93.30 R with I 2.5 o(I) 20.7 R free with I 2.5 o(I) 27.9 Average B-factor (Fab, antigen, all atoms) 15.6 A2, 15.4 A 16.4 A' Rmsd on bond distances 0.017 A Rmsd on bond angles 1.604" Rmsd on impropers 1.3570 Statistics for Table 2b Resolution range No. of residues Missing residues No. of protein atoms No. of solvent atoms No. of metal atoms No. of reflections with F 4 s(F) (all d Completness with F 4 s(F) (all data) Space group Cell dimensions R with F 4s(F) (all data) R free with F 4s(F) (all data) Average B-factor (Fab, antigen, all aton Rmsd on bond distances Rmsd on bond angles Rmsd on impropers 8.0- 1.95 A 434 16 3227 331 8 lata) 32197 (28735) 85.6% (96.0%) P 2, a=42.2; b=83.7; c=67.2 A, P= 93.30 21.3 (23.8%) 28.3 (30.1 is) 15.6 A 15.4 A 16.4 A' 0.017 A 1.604" 1.357° SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -278- Table 5 Antigen antibody contacts Residues involved in cis-peptide bond are underlined; SAS solvent accessible surface of peptide residue; Residue no. 2 is Ser, but was modelled as Ala.

Peptide residue of SAS buried number of contacts Fab residues Trp9lL, Ser93L waters Location in structure AIa2P (Ser) AIa3P Pro4P Thr6P Arg7P Pro8P 31.6 52.0 94.4 89.3 23.6 46.9 7.9 60.8 48.7 Tyr32L, Trp91L, Trp33H waters Tyr32L, Trp91L, Trp96L Trp33H, GMOM7 waters Thr6P Tyr32H, Trp33H MOM97 waters Arg7P Tyr32L waters MOM~i, Tyr32H waters Tyr32H waters Pro56L, Tyr32H, VaI95H waters Pro56L, Phe27H, Tyr32H TyrIO2H waters Li, L3, HI Li, L3 Hi, H3 antigen

HI

H3 antigen Li

HI

Hi L2, HI, H3 L2, Hi H3 A~a9P ProlOP SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -279- Table 6. Nucleotide and amino acid sequences of the light and heavy variable chains of SM3.

The numbering in this table is for convenience only and does not correspond to the conventional numbering of these sequences.

Light Chain Variable Region GAT ATC GTT Asp Ile Val 1 GTG ACT Val Thr 5 CAG GAA TCT GCA CTC Gin Glu Ser Ala Leu 10 ACC ACA TCA CCT GGT GAA Thr Thr Ser Pro Gly Glu ACA GTC ACA CTC Thr Val Thr Leu AAC TAT GCC AAC Asn Tyr Ala Asn ACT TGT CGC TCA AGT ACT GGG GCT GTT ACA ACT AGT Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser 25 TGG GTC CAA GAA AAA CCA GAT CAT TTA TTC ACT GGT Trp Val Gin Glu Lys Pro Asp His Leu Phe Thr Gly 40 144

CTA

Leu GGT GGT ACC AAC AAC Gly Gly Thr Asn Asn CGA GCA CCA GGT GTT CCT GCC AGA TTC Arg Ala Pro Gly Val Pro Ala Arg Phe 192 TCA GGC TCC CTG ATT Ser Gly Ser Leu lle CAG ACT GAG GAT GAG Gin Thr Glu Asp Glu CAT TGG GTG TTC GGT His Trp Val Phe Gly 100 GGA GAC AAG GCT GCC Gly Asp Lys Ala Ala 70 GCA ATA TAT TTC TGT Ala Ile Tyr Phe Cys 90 CTC ACC ATC ACA GGG GCA Leu Thr Ile Thr Gly Ala 75 GCT CTA TGG TAC AGC AAC Ala Leu Trp Tyr Ser Asn 288 GGA GGA ACC Gly Gly Thr

AAA

Lys 105 CTG ACT GTC CTA GGA TCC GAG Leu Thr Val Leu Gly Ser Glu 110 336 Heavy Chain Variable Region CAA GTT CAG CTG Gin Val Gin Leu 115 CAG GAG TCT GGA Gin Glu Ser Gly 120

GGA

Gly GGC TTG GTG CAA CCT GGA GGA Gly Leu Val Gin Pro Gly Gly 125 TCC ATG AAA CTC TCC TGT GTT Ser Met Lys Leu Ser Cys Val 130 135 GCC TCT GGA TTC ACT TTC AGT AAC TAC Ala Ser Gly Phe Thr Phe Ser Asn Tyr 140 SUBSTITUTE SHEET (RULE 26) WO 99/10379 PCT/GB98/02542 -280- TGG ATG AAC TGG GTC CGC CAG TCT CCA GAG AAG GGG CTT GAG TGG GTT 144 Trp Met Asn Trp Val Arg Gin Ser Pro Glu Lys Gly Leu Glu Trp Val 145 150 155 160 GCT GAA ATT AGA TTG AAA TCT AAT AAT TAT GCA ACA CAT TAT GCG GAG 192 Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu 165 170 175 TCT GTG AAA GGG AGG TTC ACC ATC TCA AGA GAT GAT TCC AAA AGT AGT 240 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser 180 185 190 GTC TAC CTG CAA ATG AAC AAC TTA AGA GCT GAA GAC ACT GGC ATT TAT 288 Val Tyr Leu Gin Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr 195 200 205 TAC TGT ACG GGA GTG GGA CAG TTT GCT TAC TGG GGC CAA GGG ACC ACG 336 Tyr Cys Thr Gly Val Gly Gin Phe Ala Tyr Trp Gly Gin Gly Thr Thr 210 215 220 GTC ACC GTC TCC TC 350 Val Thr Val Ser 225 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -28 1- Table 7 Phi and psi dihedral angles antigen.

for the bound MUCi peptidle Residue Ala 2P Ala 3P Pro 4P Asp 5P Thr 6P Arg 7P Pro 8P Ala 9P Pro loP 141 -92 160 -81 -165 -78 101 -97 16 -71 143 -65 135 -66 153 SUBSTITUTE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 -282- Table 8 SM3 MUCI van der Waals (vdW) contacts and hydrogen bonds (HB; direct and mediated through water). Residues involved in the cis -peptide bond are underlined. Ser2I' was modelled as Ala. Distance cut-off used: 4.OA for vdW contacts, 4.QA for direct HBs (weak HB above 3.5A are marked with an asterisk) and 3.5A for water mediated HBs. MC and SC refer to the main chain and side chain atoms of the SM3 antibody, respectively.

Peptide residue number of vdW contacts MC SC Fab residues CDR Hydrogen bond peptide Fab Distance (k) Ser2P (Ala) Ala3P Pro4P 1 4 5 4 1 10 6 6 2 WvIL, s93L y32L w33H R 5 2

H

W91L, W96L w33H Y32H,

W

3

H

L3 0 NEI (W9IL) 0 0 ($93) Li L3 Hi H2 0 -water NilI(OH m Li 13 N -NEI (W 9 1L) 2.63 3.46 2.90, 2.98 3.88* 3 19 081 NEI (W33H) 062 N (33H) 082 water 0 (W 31 08 1 water 0 (N 3

H)

3.89' 3.18 2.71, 2.78

N

3 t1

H

2.48, 2.66 3.35, 2.66 3 2.71, 2.89

Q=

Hi 082 -water -0 3 1 H{3 0 N2QM! H3 082 -water -N (V 5 H3 082 water N QM! 3.01 3.08, 2.73 SUBSTITE SHEET (RULE WO 99/10379 WO 99/ 0379PCT/GB98/02542 Thr6P y32L N 5 3

L

-28 3- H3 0 -water -N(Q961) Li L2 0 water 05 1 (NSJL) HI Ne 0 (N' 3 1

H)

M1~2 N82 (N 31

H)

Nil 2 051 (N 3 1

H)

H3 0 -water -N (n HI1 0 0 1 n(y 3 1

H)

Arg7P 1 9 N 31H. Y3 2

H

Pro8P Ala9P Pro lop Total 5 G 96

H

P56L v 9 51 2.96, 2.73 2.94, 3.25 3.51 3.34 3.98' 2.70, 2.73 2.43 3.9 1 3.36 N OI~ (Y 32 11 N Oil (Y'H) P56L F 271 y 321 Ll L2, L3,H11, H3 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 9910379PCT/GB98/02542 -284- Table 9 NSA buried upon SM3 MUdl peptide antigen complex formation. MSA has been calculated for individual SM3 CDRs and the peptide antigen alone. Residues involved in non-Proline cis-peptide, bond are underlined.

Residues buried MSA'buried total buried MSA A. SM3 light chain Li: Ser3OL 2.3 0.4 Tyr32L 48.5 Li: 26-32 (10 residues) 50.8 9.9 L2: Asn53L 4.1 0.8 3.0 0.6 Pro56L 33.8 6.6 L2: 50-56 (7 residues) 40.9 L3: Trp9lL 44.7 8.7 Ser93L 21.1 4.1 Trp96L 16.8 3.3 12: 89-96 (7 residues) 82.6 16.1 Total light chain 174.3 34.0 B. SM3 Heavy chain Phe27H 20.7 Thr28H 3.9 0.8 Hi: Asn3lH 34.4 6.7 Tyr32H 65.6 12.8 Trp33H 58.4 11.4 2.9 0.6 HI: 31-35 (5 residues) 161.3 31.5 H2: Arg52H 9.6 1.9 Leu52aH 10.7 2.1 H-2: 52-65 (17 residues) 20.3 1H3: VaI95H 40.8 GIY96H 19.8 3.8 Gln97H 43.4 SUBSTITUTE SHEET (RULE 26) WO 99/10379 WO 99/ 0379PCT/GB98/02542 -28 Ala1O1H Tyr1O2H H3: 95-102 (6 rsidues) Total heavy chain Total SM3 Fab C. MUCI peptide Ala2P Ala3P Pro4P Thr6P Arg7P Pro8P Ala9P ProlOP Total MUCI peptide 5.3 23.0 132.3 338.5 512.8 25.8 66.0 38.0 32.2 69.7 82.5 23.5 65.2 20.7 36.7 64.7 8.8 7.4 16.1 19.0 5.4 15.1 4.8 14.9 433.2 'MSA calculated according to MS using a probe radius of 1.7 A.

program (Connolly, 1983) SUBSTITUTE SHEET (RULE 26) Table 10 SAA buried upon antibody-peptide complex formation, calculated using PDBAREA' Fab PDB Peptide Fab name code' Total SAA hydrophobic polar SAA hydrophobic Total SAA hydrophobic polar SAA hydrophobic buried SAA (A 2 polar buried (A 2 SAA polar 59.1 lacy 614 462 152 3.04 437 257 180 1.43 C3 Ifpt 626 277 349 0.79 439 245 194 1.26 50.1 iggi 685 514 171 3.00 456 291 165 1.76 17/9 Ihim 626 394 232 1.70 464 232 232 1.00 likf likf 3 702 600 102 5.88 557 358 199 1.80 MN12H2 Impa' 699 326 373 0.87 561 333 228 1.46 TE33 Itet 718 425 293 1.45 512 263 249 1.06 2H111 2hlp 695 529 166 3.19 589 400 189 2.12 F11.2.32 2hrp 657 447 210 2.13 527. 310 217 1.43 B1312 2igf 677 427 250 1.71 485 '358 127 2.82 SM3 lsm3 606 392 214 1.83 480 318 162 1.96 'PDBAREA Islam, ICRF) calculates SAA using the algorithm of Lee Richards (1971). For calculations a probe with a standard 1.4 A radii was used. Hydrophobic SAA includes C and S atoms, polar SAA all other atoms (only non-hydrogen atoms used for calculations). The SAA is different from the MSA calculated by MS (Connolly, 1983) 2 According to Brookhaven Data Bank (Bernstein et al., 1977) SCyclic peptide with non-standard residues 4 N-terminal residue in peptide is THC N-methylcarbonyl threonine, and C- termnial is CYF S-(4-Fluoresceinylcarbamoyle-methyl)-cysteinyl.

Claims (26)

1. Use of the structure factors obtainable by subjecting a crystal comprising at least an epitope binding fragment of the SM3 antibody, bound to a peptide recognised by the epitope binding site of SM3 to X-ray diffraction measurements, to identify, design or modify a chemical entity.

2. Use of the structural coordinates obtainable by subjecting a crystal comprising at least the epitope binding fragment of the SM3 antibody, bound to a peptide recognised by the epitope binding site of SM3 to X-ray diffraction measurements and deducing the structural coordinates from the diffraction measurements, to identify, design or modify a chemical entity

3. Use according to claim 1 or claim 2 in which the fragment of the SM3 antibody is the Fab fragment obtainable by digesting SM3 with papain.

4. Use of the structure factors or structural 20 coordinates obtainable by subjecting a crystal comprising a fragment of SM3 bound to a peptide recognised by the peptide binding site of SM3 to X-ray diffraction measurements to identify, design or modify a chemical Sentity, wherein the fragment of SM3 comprises at least one 25 amino acid insertion, deletion or substitution and retains the ability to bind said peptide.

5. Use according to any one of the preceding claims in which the peptide comprises the sequence Pro-Asp-Thr- Arg-Pro.

6. Use according to claim 5 in which the sequence is C/JRA 1 Thr-Ser-Ala-Pro-Asp-Thr-Arg-Pro-Ala-Pro-Gly-Ser-Thr. S 7. Use of the structure factors as shown in Table 1 P:\OPER\Fas\XX711-98-spcdoc-l 1/06/02 288 to identify, design or modify a chemical entity.

8. Use of the structural coordinates as shown in Table 2a or 2b to identify, design or modify a chemical entity.

9. Use according to any one of the preceding claims of the structure factors or structural coordinates to identify or design a mimic of SM3. Use according to claim 9 in which the mimic of SM3 has a desired association with aberrantly glycosylated MUC1.

11. Use according to claim 10 in which the desired association is binding affinity with aberrantly glycosylated MUC1 which is higher than the binding affinity of SM3 for aberrantly glycosylated MUC1.

12. Use according to any one of claims 9 to 11 in which the mimic of SM3 is obtainable by modification of Seither whole SM3 or a fragment of SM3.

13. Use according to claim 12 in which the modification is the replacement of Proline 56 of SM3. 20 14. Use according to any one of claims 1 to 8 to identify or design a mimic of the peptide epitope of MUC1 recognised by SM3. Use of the mimic of the peptide obtained in the use of claim 14 to produce a mimic of SM3 which has a 25 desired association with aberrantly glycosylated MUC1.

16. Use according to claim 15 in which the mimic of SM3 is an antibody.

17. Use according to claim 16 in which the antibody is produced in a method comprising vaccinating an animal or human with the mimic of the peptide. R18. Use according to claim 14 in which the mimic of Sthe peptide can P:\OPER\Fls\8X71- 9K-sp.doc-l l16/)2 289 prevent or decrease an immune response.

19. Use according to any one of claims 14 to 18 in which the mimic of the peptide is obtainable by a chemical modification of a peptide.

20. Use according to any one of claims 14 to 19 in which the mimic of the peptide is a glycosylated peptide.

21. A mimic of the peptide epitope of MUC1 recognised by SM3 which mimic is obtained by the use of any one of claims 1 to 8.

22. A mimic of SM3 which mimic is obtained by the use of any one of claims 1 to 13 and 15 to 17.

23. An engineered antibody having a conformation comprising an engineered non-proline cis peptide bond.

24. A crystal comprising at least an epitope binding fragment of the SM3 antibody bound to a peptide recognised by the epitope binding site of SM3. A method of producing the crystal of claim 24 which comprises crystallising the fragment of SM3 bound to the peptide in the presence of cadmium and recovering said 20 crystal.

26. A machine readable data storage medium comprising a data storage material encoded with machine readable data which when read by an appropriate machine is capable of displaying a three dimensional representation of a crystal as defined in claim 24.

27. Use of a mimic of SM3, a mimic of the peptide epitope of MUC1 recognised by SM3 or an engineered antibody according to claims 21 to 23 in the production of a S•medicament for use in a method for anti-cancer treatment of the human or animal body by surgery or therapy or of cancer y STF4 diagnosis practised on the human or animal body. S 28. A method of cancer diagnosis or anti-cancer P:\OPER\F9is\711 -9X-spe.doc-Ill /I/02 290 therapy comprising administering to a human or non-human animal in need thereof an effective non-toxic amount of a mimic of SM3, a mimic of the peptide epitope of MUC1 recognised by SM3 or an engineered antibody according to any one of claims 21 to 23.

29. A product comprising a mimic of SM3 according to claim 22 and an anti-tumour agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.

30. Use of a mimic of peptide epitope of MUC1 epitope recognised by SM3 according to claim 21 in the production of a medicament for treating a disease caused by an immune response.

31. A method of therapy of a disease caused by an immune response comprising administering to a human or non- human animal in need thereof an effective non-toxic amount of a mimic of the peptide epitope of MUC1 recognised by SM3 according to claim 21.

32. Use of the structure factors and/or structural 20 coordinates defined in any one of claims 1 to 8 to solve the structural coordinates of a crystal.

33. Use according to any one of claims 1 to 20, 27, and 32 substantially as hereinbefore described with reference to the drawings and/or examples. DATED this 1 1 t h day of June 2002 Imperial Cancer Research Technology Limited by DAVIES COLLISON CAVE ST Patent Attorneys for the Applicants EDITORIAL NOTE NO. 88711/98 The following 4 pages are Indications Relating to a Deposited Micro-organism and are followed by the drawings. Applicant's or agent's file N73466A International application PC GB98/02542 referencenumber N73466APC/GB98/02542 INDICATIONS RELATING TO A DEPOSITED MICROORGANISM (PCT Rule 13bis) A. The indications made below relate to the microorganism referred to in the description on page 1 ,line 14-16 B. IDENTIFICATIONOFDEPOSIT Further deposits are identified on an additional sheet Name of depositary institution European Collection of Animal Cell Cultures (ECACC) Address of depositary institution (including postal code and country) Porton Down Salisbury Wiltshire SP4 OJG Great Britain Date of deposit Accession Number 7 January 1987 87010701 C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet The additional 7 sheets include authorisations and deposit receipts. D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the indications are notforalldesignated States) E. SEPARATE FURNISHING OFINDICATIONS(leaveblankifnotapplicable) The indications listed below will be submitted to the International Bureau later (specify the general nature of the indications "Accession Number of Deposit") Forreceiving Office use only For International Bureau use only 7 This sheet was received with the international application This sheet was received by the International Bureau on: 2 1 DEC 1998 Authorized officer Authorized officer Form PCT/RO/134 (July 1992) olk PCT/GB98/02542 DP/A/II/12 page 14 BUDAPEST TREATY ON THE INTERNATIONAL RECOGNITION OF THE DEPOSIT OF MICROORGANISMS FOR THE PURPOSES OF PATENT PROCEDURE INTERNATIONAL FORM TO Dr. Joyce Taylor-Papadiitriou Imperial Cancer Resear h Fund Laboratories P.O. Box No. 123 Lincoln's Inn Fields London, WC2A 3PX NAME AND ADDRESS OF DEPOSITOR RECEIPT IN THE CASE OF AN ORIGINAL DEPOSIT issued pursuant to Rule 7.1 by the INTERNATIONAL DEPOSITARY AUTHORITY identified at the bottom of this page I. IDENTIFICATION OF THE MICROORGANISM Identification reference given by the Accession number given by the DEPOSITOR: INTERNATIONAL DEPOSITARY AUTHORITY: H-SM3 87010701 II. SCIENTIFIC DESCRIPTION AND/OR PROPOSED TAXONOMIC DESIGNATION The microorganism identified under I above was accompanied by: L Y a scientific description Sa proposed taxonomic designation (Mark with a cross where applicable) III. RECEIPT AND ACCEPTANCE This International Depositary Authority accepts the microorganism identified under I above, which was received by it on7.1.87. (date of the original deposit)l IV. INTERNATIONAL DEPOSITARY AUTHORITY ::ame: Dr. A. Doyle Curator, ECACC Signature(s) to represent Authority or Date: 23rd of person(s) having the power the International Depositary of authorized official(s): Ma~ 1987 Address: PHLS CAMR, ECACC Porton fnwn~ S~mlih~v~ Wi1-~, Where Rule 6.4(d) applies, such date is the date on which the status of international deposital authority was acquired; where a deposit made outside the Budapest Treaty after the acquisitiol of the status of international depositary authority is converted into a deposit under the Budapest Treaty, such date is the date on which the microorganism was received by the international depositary authority. Form BP/4 (sole page) PCT/GB98/02542 BUDAPEST TREATY ON THE INTERNATIONAL RECOGNITION OF THE DEPOSIT OF MICROORGANISMS FOR THE PURPOSES OF PATENT PROCEDURE INTERNATIONAL FORM r[ Dr. Joyce Taylor-Papadimit iou Imperial Cancer Research Fund Laboratories P.O. Box No. 123 Lincoln's Inn Fields London WC2A 3PX NAME AND ADDRESS OF THE PARTY CO WHOM THE VIABILITY STATEMENT IS ISSUED VIABILITY STATEMENT issued pursuant to Rule 10.2 by the INTERNATIONAL DEPOSITARY AUTHORITY identified on the following page C. DEPOSITOR II. IDENTIFICATION OF THE MICROORGANISM lame: Dr. Joyce Taylor-Papadimitriou kddress: Imperial Cancer Research Fund Labs. P.O. Box No. 123 Lincoln's Inn Fields London, WC2A 3PX Accession number given by the INTERNATIONAL DEPOSITARY AUTHORITY: 87010701 Date of the deposit or of the transfer: 7th January 1987 CII. VIABILITY STATEMENT 'he viability of the microorganism identified under II above was tested 2 n On that date, the said microorganism was 3 viable __3 no longer viable L Indicate the date of the original deposit or, where a new deposit or a transfer has been made, the most recent relevant date (date of the new deposit or date of the transfer), In the cases referred to in Rule 10.2(a) (ii) and (iii), refer to the most recent viability test. Mark with a cross the applicable box. Form BP/9 (first page) PCT/GB98'/02542 CON'DITIONS UNDER WHICH THE VI1ABILITY TEST HAS BEEN PERFORMED 4 INTERNATIONAL DEPOSITARY AUTHORITY ame: .ddress:. Dr. A. Doyle6, Curator, ECACCC P9LS CAMR,. ECACC Porton Down Salisbury, Wilts SIgnature(s) of person(s) having the power to represent the International Depositary Authority or of authorized official(s): Date: 2r 18 IFill in if the Information has been requested and if the results of the test were negative Form BP/9 (second and last page)