SK9762000A3 - Modified deacetoxycephalosporin c synthase (daocs) and x-ray structure - Google Patents

Abstract

Three-dimensional crystal structure(s) of deacetoxycephalosporin C synthase (DAOCS) are described. The X-ray co-ordinates provide precise 3-dimensional information of amino acids within the structure of DAOCS. Some of these are in complexes with iron and/or substrates. Information from the structures is used to modify enzymes of the cephalosporin biosynthesis pathway including DAOCS, deacetylcephalosporin C synthase DAOC/DACS, such that they accept unnatural substrates (e.g. penicillins G, V) in order to improve the production of beta-lactam antibiotics. The structures may be used to predict the structures of other 2-oxoglutarate dependent enzymes, thereby allowing the design of inhibitors, and new catalysts for the production of e.g. oxidised amino acids/peptides. Specific modifications of amino acid residues are proposed and exemplified.

Description

445 Modified deacetoxycephalosporin C synthesis (DAOCS) and structure of X-rays

Technical field

Penicillin and cephalosporin antibiotics are produced either directly by fermentation or by modification of fermentation-derived substances containing a beta-lactam ring.

BACKGROUND OF THE INVENTION

The method of penicillin and cephalosporin biosynthesis has been extensively studied and investigated (JE Baldwin and CJ Schofield, "The Chemistry of β-lactams" (Ed. Ml Page), Chapter 1, Blackie, London 1992; Ingolia and Queener, Med. Res. 1989, 9, 245-264; Aharonowitz, Cohen and Martin, Ann Rev. Microbiol., 1992, 46, 461-495; Schofield, Bycroft, Baldwin, Hajdu, Roach, "Current Opinion in Structural Biology", 1997, 7, 857-864) and includes the following steps (Figure 1).

Conversion of a tripeptide: L-Ô-α-aminoadipoyl-L-cysteinyl-D-valine (ACV) to isopenicillin N in a step catalyzed by isopenicillin N synthesis (IPNS). This year is common for both penicillin biosynthesis and cephalosporin biosynthesis.

2. In some organisms (e.g., Penicillium chrysogenum and Aspergillus nidulans), isopenicillin N is converted by exchanging its L-δ-α-aminoadipoyl side chain into penicillins with other side chains, which are normally more hydrophobic than the isopenicillin N side chain. amidohydrolase / acyltransferase. Examples of penicillins produced by this biosynthesis method include penicillin G (which has a phenylacetyl side chain) and penicillin V (which has a phenoxyacetyl side chain). These hydrophobic penicillins can be commercially produced by fermentation under appropriate conditions.

3. In other organisms (e.g. Streptomyces clavuligerus and Cephalosporium acremonium), isopenicillin N is epimerized to penicillin N. This reaction is catalyzed by the epimerizing enzyme.

4. In some organisms (eg S. clavuligerus and C. acremonium) penicillin N is converted to deacetoxycephalosporin C (DAOC) This reaction is catalyzed by deacetoxycephalosporin C synthesis (DAOCS) in some organisms (eg Streptomyces clavuligerus) and deacetoxy / deaoretylcephospho synthesis (DAOC / DACS) in other organisms (e.g., C. acremonium).

5. In some organisms (e.g., S. clavuligerus and C. acremonium), deacetoxycephalosporin C (DAOC) is converted to deacetylcephalosporin C (DAC). This reaction is catalyzed by deacetylcephalosporin C synthesis (DACS) in some organisms (e.g. S. clavuligerus) and deacethoxy / deacetylcephalosporin C synthesis (DAOC / DACS) in other organisms (e.g. C. acremonium).

Additional biosynthesis steps may also occur that provide additional cephalosporin derivatives, e.g. in C. acremonium, deacetylcephalosporin C can be converted to cephalosporin C and in Streptomyces spp. deacetylcephalosporin C can be converted to cefamycin C.

Fermented penicillins, cephalosporins and their biosynthesis intermediates are useful as antibiotics or as intermediates in the production of antibiotics. Penicillins with a hydrophobic side chain may be useful for the preparation of cephalosporins or semi-products used for the preparation of cephalosporins, e.g. penicillins (including penicillin G and penicillin V) may be useful for the preparation of C-3 exomethylencephams, which may be useful as intermediates in the preparation of commercial antibiotics, e.g. Cephachlor.

The enzymes isopenicillin N synthesis, deacetoxycephalosporin C synthesis, deacetylcephalosporin C synthesis and deacethoxy / deacetylcephalosporin C synthesis are members of the extended group Fe (II) utilizing the enzymes oxidase and oxygenase. Most of this group (including deacetoxycephalosporin C synthesis, deacetylcephalosporin C synthesis and deacethoxy / deacetylcephalosporin C synthesis) utilizes 2-oxoacid (usually 2-oxoglutarate) as a cosubstrate alongside dioxygen and a "base" substrate (eg, penicorinin C in case of deacethoxy C). Since isopenicillin N synthesis does not use 2-oxoglutarate, it has a substantially different mechanism to that of 2-oxoglutarate-dependent oxygenases, thereby creating a significantly different active site.

SUMMARY OF THE INVENTION

The present invention is based on the determination of the three-dimensional crystal structure of deacetoxycephalosporin C synthesis and the information and developments resulting therefrom. X-ray coordinate coordinates provide very detailed three-dimensional information about the relationships between amino acid residues in the deacetoxycephalosporin C synthesis structure and about the Fe-cofactor binding methods and deacetoxycephalosporin C synthesis substrates. The structure allows the modification of deacetoxycephalosporin C synthesis and related penicillin and cephalosporin biosynthesis enzymes (including deacetylcephalosporin C synthase, and deacethoxy / deacetylcephalosporin C synthesis) to alter their substrate and product selectivity. Since the structures of deacetoxycephalosporin C synthase are the first of a group of 2-oxoglutarate-dependent dioxygenases, these also allow the design of novel inhibitors of this family of enzymes. Partial reviews of the structures of manganese, iron, and ACV isopenicillin N complexes have been reported in the past (Roach et al., Nature, 1995, 375, 700-704, Roach et al., Nature, 1997, 387, 827). Structures defined by the coordinates of their X-rays, isopenicillin N complexes with manganese, iron and ACV, and / or analog substrates have been reported by Baldwin, Hajdu, Roach, Hensgens, Clifton, GB 9621486.1- (Oxygenase Enzymes and Method).

Processes for the production of 7-aminodeacetoxycephalosporin C (7-ADCA) have been developed in which recombinant P. chrysogenum chains into which the deacetoxycephalosporin C synthase gene has been introduced are used to produce cephalosporins. In particular, when adipic acid is added to these recombinant chains, adipoyl-6-ΑΡΑ is produced, which is converted by deacetoxycephalosporin C synthase to adipoyl7-ADCA, whose adipoyl side chain can be removed (EPA-A-0532341, Shibata et al., Bioorg. Med. Chem. Letts, 1996, 6, 1579-1584).

The sequence of the isopenicillin N gene (and thus the amino acid sequence) is similar, but is significantly different with respect to those of deacetoxycephalosporin C synthase, deacetylcephalosporin C synthase, deacethoxy / deacetylcephalosporin C synthase. It is likely that the overall elements of the layer (i.e., significant elements with a three-dimensional structure) of these enzymes will be retained, but that the active site composition will be significantly different. Preserved structural elements are likely to include beta-barrel "shaking waves" of the nucleus and certain alpha-spirals (including alpha-spiral-10 as defined by Roach et al., Nature, 1995, 375, 700-704). The degree of similarity is insufficient to define the exact structure of the deacetoxycephalosporin C synthesis, the deacetylcephalosporin C synthesis or the deacethoxy / deacetylcephalosporin C synthesis from the isopenicillin N synthesis structure. No models of deacetoxycephalosporin C synthesis, deacetylcephalosporin C synthesis or deacethoxy / deacetylcephalosporin C synthesis based on the isopenicillin N synthase structure were reported. No detailed studies on substrate binding of these enzymes have been reported. One report (WO 97/20053) claims the use of products based on the modification of certain residues of deacetoxycephalosporin C synthase for improved conversion of penicillin G to phenylacetyl (G) -7-aminocephalosporinic acid.

The three-dimensional structure of deacetoxycephalosporin C synthase is defined by the x-ray coordinate coordinates shown below (Structure A).

Also, the highly resolved crystal structure of the complex of prokaryotic deacetoxycephalosporin C synthase from S. clavuligerus with Fe (II) and 2-oxoglutarate (Structure B) is also subdivided.

In part, the present invention relates to the use of the structures of deacetoxycephalosporin C synthase to generate modifications thereof or modifications of deacetylcephalosporin C synthase or deacethoxy / deacetylcephalosporin C synthase so that the modified enzymes catalyze the conversion of non-natural penicillins (e.g. with uncontrollable characters. Other aspects of the invention relate to the use of the structure of deacetoxycephalosporin C synthase for producing non-natural products in microorganisms. Such products include exomethylene-cephalosporins, with or without an alpha-aminoadipoyl or hydrophobic side chain (e.g., phenylacetyl or phenoxyacetyl). Thus, one aspect of the present invention relates to the use of a deacetoxycephalosporin C synthase structure for modifying deacetoxycephalosporin C synthase (or the proximal enzymes deacetylcephalosporin C synthase or deacethoxy / deacetylcephalosporin C synthase) to:

- allow the enzyme to accept (or accept much more effectively) non-natural penicillin substrates for the preparation of new or commercially valuable antibacterial agents,

allow a modified enzyme for the production of unnatural substances (eg.

exomethylene-cephams) or optimized the production of minor products (e.g. 3β-hydroxycephams) for use as antibacterial agents or as semi-products in the preparation of antibacterial agents or commercially valuable compounds.

In another aspect, the present invention provides modified enzymes that are based on the application of the above techniques. These are enzymes having a significant (as defined below) sequence and therefore structural similarity to deacetoxycephalosporin C synthesis. Then, the structures of these enzymes can be predicted based on the structures of the deacetoxycephalosporin C synthesis. Preferably, the sequence similarity / identity will be between most of the modified enzyme and most of the deacetoxycephalosporin C synthase. Previous sequence comparisons (Roach et al., Nature, 1995, 375, 700) using a pairwise sequence comparison method followed by single chain analysis of clusters show that the isopenicillin N synthase cluster, deacetox / cephalosporin C synthase, deacetylcephalosporin C synthase and deacetoxy / deacethoxy cephalosporin with standard deviations it has a score of> 5.0 (Barton and Sternberg, J. Mol. Biol., 1987, 198, 327). Grooving above 5.0 and preferably above 6.0 determines that sequences of sequences will be correctly aligned in all or most protein secondary structural elements (Barton, Methods in Enzymol., 1S90, 183, 403); then they have significant sequence similarity and hence structures. Note that there are other criteria that can be used to determine significant sequence similarity, for example,% identity or% similarity of amino acids having side chains with similar physicochemical properties (Barton and Sternberg, J. Mol. Biol., 1987, 198, 327 ). Thus, by comparing the sequences one can predict the structure of one enzyme (e.g., deacetylcephalosporin C synthase or deacethoxy / deacetylcephalosporin C synthase) from another very close enzyme (e.g., deacetoxycephalosporin C synthase). Furthermore, it has been recognized that although the two enzymes may have structures in which the secondary structural elements are largely or completely conserved, differences in the structure of the two enzymes may be based on the side chains of the amino acids constituting the secondary structural elements. The effect of these differences, which alter the substrate / product selectivity of the compared enzymes, is predictable when the three-dimensional structure of one of the enzymes is known

In another aspect, the invention provides an enzyme having significant (as defined herein) sequence similarity to deacetoxycephalcisporin C synthesis wherein the site of binding of the penicillin N or deacetoxycephalosporin C side chain is modified and at least one of the following sites of at least one amino acid residue is changed to another amino acid residue or deleted: Thr72, Arg74, Arg75, Glu156, Leu158, Arg160, Arg162, Leu186, Ser187, Phe225, Phe264, Arg266, Asp301, Tyr302, Val303, Asn304; and / or at least one additional amino acid residue is incorporated into region 300-311; with the proviso that other residues interacting with the above may be altered to accommodate the change in one of the above residues.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Biosynthesis method for penicillins and cephalosporins

Figure 2 is an overview of the active site of deacetoxycephalosporin C synthesis showing iron-bound 2-oxoglutarate and the proposed binding of penicillin N. Interactions with the side chains of certain amino acid residues are indicated by arrows.

Structure A is a three-dimensional structure of deacetoxycephalosporin C synthase.

Structure B is a highly resolved crystal structure of procarytotic deacetoxycephalosporin C synthase from S. clavuligerus as a complex with Fe (II) and 2-oxoglutarate.

The peptide sequence of deacetoxycephalosporin C synthase (with the numbering used herein) is set out below:

DETAILED DESCRIPTION OF THE INVENTION

Modifications of the above species will allow the extension of penicillin V or penicillin G to the corresponding cephalosporins. To achieve this, it is desirable to increase the kcat / Km of the mutant compared to the untreated type of deacetoxycephalosporin C synthase. The kinetic results indicate that the apparent kcat values for penicillin N and penicillin G are similar, but the Km is much higher for penicillin G. Thus, based on these analyzes, a decrease in the deacetoxycephalosporin C synthase binding constant for penicillin G should allow an increase in kcat / Km for penicillin G .

The side chain binding point of deacetoxycephalosporin C synthase is created from residues from different parts of the peptide chain so that probably more than one residue will need to be altered to create a better penicillin G / V expander. However, some residues are more important than others. Examination of the interactions between the last few C-terminal residues (Thr-308 to Ala-311) of one molecule of deacetoxycephalosporin C synthase and the active site of another in the crystal structure suggests a penicillin core binding method as shown in Figure 2 of the accompanying drawings. The C-3 carboxyl group foam is likely to occupy an analogous position to that of Ala-311 from the symmetry of the molecule at the active site, creating electrostatic interactions with Arg-162 and Arg-160. The Arg160 side chain can also form hydrogen-linked interactions with β-lactam-carbonyl.

It should be understood that protein specificity is generally controlled by more than one amino acid. More than one of the mutation changes proposed below is likely to be required to alter protein specificity in the main way, although each mutation will contribute to this. In view of this, preferred residues for modifying penicillin expansion are as follows:

(a) Arg-266

This residue binds to the α-aminoadipate side chain of the natural substrate and can be changed to a more residue; hydrophobic character, e.g. Phe, Ala, Val, Leu, Ile.

b) Thr-72

This is to be changed to a hydrophobic residue such as Val, Leu, Ile, Phe, Ala to help bind the hydrophobic side chain of pencilin G. It will be effective in combination with other mutants.

c) Arg-74

It can be usefully changed to a neutral hydrophobic residue (Phe, Tyr, Val, Leu, Ile, Ala). In addition, modification of Arg-75 may be necessary as it forms a hydrogen bonded network with Arg-74.

d) Glu-156

This residue binds to the α-aminoadipate side chain. Will be changed to one of Ala, Val, Leu, Ile, Phe, Tyr, Trp, Asn, Aln, Ser.

e) The Leu-158, Asn-301 and Tyr-302 side chains form part of the penicillin side chain binding point and can be usefully modified to be more hydrophobic in nature.

f) Asn-304

This residue binds the side chain amide linkage to the foam core. The modification is effective for expanding penicillins with shortened side chains or without side chains (e.g., Asp or Glu in 6-Apa).

Note that other changes may be used to construct part or all of the side chain binding point through hydrogen bonding or other interactions.

Incorporating or deleting residues into the deacetoxycephalosporin C synthase sequence may also be useful in constructing a hydrophobic penicillin side chain binding point. Incorporation of hydrophobic residues into the C-terminal region (residue 300-311 and especially 301-303) may aid in the construction of the hydrophobic point of attachment of the penicillin side chains.

In another aspect, the present invention carries out an enzyme having significant (as defined herein) sequence similarity to deacetoxycephalosporin C synthesis, wherein the penicillin / cephalosporin binding site of penicillin N or deacetoxycephalosporin C is modified and at least one of the following amino acid residues is altered or deleted:

Ile88, Arg160, Arg162, Phe164, Met180, Thr190, Ile192, Phe225, Pro241, Val245, Val262, Phe264, Asn304, lle305, Arg306, Arg307; and / or at least one additional amino acid residue is included in the region of 300-311; with the proviso that other residues interacting with the above may be altered to accommodate the change in one of the above residues.

Further discussion of this aspect can be found in Nature, vol. 394, pages 805-809 published on August 20, 1998 and incorporated herein by reference.

Another aspect of the present invention relates to the use of the structure of deacetoxycephalosporin C synthase to modify its active sites (or that which is structurally similar to 2-oxoglutarate-dependent dioxygenase) so that the modified enzyme accepts beta-lactam-free substrates to produce significant oxidized compounds. Oxidized amino acids (e.g.

4-hydroprolines, hydrolysines, hydroxyaspartic acids and others) are useful as synthetic intermediates for the production of important substances.

The use of the structure of specific residues of deacetoxycephalosporin C synthesis may be targeted for modification so that a modified enzyme can be used to produce oxidized amino acids or peptides. The method may include modification of the following residues:

Arg74, Glu156, Leu158, Arg160, Arg162, Leu186, Ser187, Phe225, Phe264, Arg266, Asp301, Tyr302, Val303, Asn304, Ile88, Arg162, Phe164, Met180, Thr190, Ile192, Pro241, Val245, Val545, Val545, Arg307.

Another aspect of the present invention relates to the use of a deacetoxycephalosporin C synthase structure for the design of selective 2-oxoglutarate-dependent dioxygenase inhibitors. The 2-oxoglutarate-dependent dioxygenase prolyl 4-hydrolase was the target of inhibition for the therapeutic treatment of fibrotic diseases (e.g. liver cirrhosis, arthritis). However, no inhibitors have clinical use, probably because it is difficult to achieve selective inhibition of the target enzyme to inhibit several other enzymes (including 2-oxoglutarate-dependent enzymes). The structure of deacetoxycephalosporin C synthase provides a chemical scheme for the design of 2-oxoglutarate-dependent dioxygenase inhibitors.

Two high-resolution crystal structures of deacetoxycephalosporin C synthase from S. clavuligerus are depicted below: the structure of the iron-free apoenzyme (Structure A) and the structure of the complex with Fe (II) and 2-oxoglutarate (Structure B). The result suggests a mechanism by which the enzyme-Fe (II) complex reacts with 2-oxoglutarate and dioxygen to provide reactive feryl species, a procedure common to many blood-free oxygenases. Other notable 2-acid-dependent iron-containing enzymes are prolyl hydroxylase, found in collagen biosynthesis, giberelin 3β-hydroxylase, a mutation that affects plant length, and clavaminic acid synthase, involved in the β-lactamase inhibitor biosynthesis, β-lactam inhibitor. In the group of 2-acid-dependent enzymes, deacetoxycephalosporin C synthases belong to a subgroup whose members show sequence similarity to isopenicillin N synthesis and 1-aminocyclopropane-1-carboxylate oxidase (ethylene-forming enzymes), enzymes not used in catalysis 2.

The iron-free deacetoxycephalosporin C synthase form crystallizes in the R3 space group as a crystallographic trimer. The backbone of the protein folds into the retained shaking wave of the core flanking the spirals.

Coordinates and structure factors were stored in the Protein Data Bank (inputs 1xrg, and rlrxgsf for Fe (II) -2-oxoglutarate complex).

\ WO 99/33994

PCT / GB9S / 03860

Met Asp Thr Thr wall for Thr Phe .ser Leu 10 Ala Glu Leu gin gin Gly Leu His gin Asp 20 Glu Phe Arg Arg Cys Leu Arg Asp Lys Gly 30 Leu Phe Tyr Leu Thr Asp Cys Gly Leu Thr 40 Asp Thr Glu Leu Lys Ser Ala Lys Asp Leu 50 wall Ile Asp Phe Phe Glu His Gly Ser Glu 60 Ala Glu Lys Arg Ala wall Thr Ser for wall 70 for Thr Met Arg Arg Gly Phe Thr Gly Leu 80 Glu Ser Glu Ser Thr Ala gin Ile Thr same time 90 Thr Gly Ser Tyr Ser Asp Tyr Ser Met Cys 100 Tyr Ser Met Gly Thr Ala Asp same time Leu Phe 110 for Ser Gly Asp Phe Gly Arg Ile Trp Thr 120 gin Tyr Phe Asp Arg gin Tyr Thr Ala Ser 130 Arg Ala wall Ala Arg Glu wall Leu Arg Ala 140 Thr Gly Thr Glu for Asp Gly Gly wall Glu 150 Ala Phe Leu Asp Cys Glu for Leu flight Arg 160 Phe Arg Tyr Phe for gin wall for Glu His 170 Arg Ser Ala Glu Glu gin for Leu Arg Met 180 Ala for His Tyr Asp Leu Ser Met wall Thr 190 Leu Ile gin gin Thr for Cys Ala same time Gly 200 Phe wall Ser Leu gin Ala Glu wall Gly Gly 210 Ala Phe Thr Asp Leu for Tyr Arg for Asp 220 Ala wall Leu wall Phe Cys Gly Ala Ile Ala 230 Thr Leu wall Thr Gly Gly gin wall Lys Ala 240 for Arg His His wall Ala Ala for Arg Arg 250 Asp gin Ile Ala Gly Ser Ser Arg Thr Ser 260 Ser wall Phe Phe Leu Arg for same time Ala Asp 270 Phe Thr Phe Ser wall for Leu Ala Arg Glu 280 Cys Gly Phe Asp wall Ser Leu Asp Gly Glu 290 Thr Ala Thr Phe gin Asp Trp Ile Gly Gly 300 same time Tyr wall same time Ile Arg Arg Thr Ser Lys 310

Ala

311

PCT / GB98 / 03860

WO 99/33994

- 12 STRUCTURE A

90.00 90.00 120.00

CRYST1

106.400

106.400

71.100

SCALE1 0.009398 0.005426 0.000000 0.000000 SCALE2 0.000000 0.010852 0.000000 0.000000 SCALE3 0.000000 0.000000 0.014065 0.000000

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PC17GB9S'03860

.-. TOM ANISOU j 1 N AMET AMET 1 1 30 4 3 4 8315 - 13 - 10.641 2319 59.873 0.542 44.21 6203 -614 ^x 34> 5 4 - 7 8 1 ATÓM C A AMET 1 30.965 11 .769 59.065 0.542 3 9.90 Anisa - \ 4th C A AMET 1 9037 3006 3117 - 7 8 ó -1026 2 9 6 ATÓM 3 C AMET 1 30.472 12.900 59956 0.542 8.97 Anisa 3 C AMET 1 4807 3113 3 386 -421 -2189 -119 ATÓM 4 ABOUT AMET 1 29.961 12. 670 6 L.055 0.542 2 8.12 Anisa 4 ABOUT AMET 1 3925 2381 4 3 77 -402 -1097 7 4 ATÓM 5 CB AMET 1 29.970 11.328 58.023 0.542 3 4.85 Anisa 5 CB AMET 1 7877 3 692 1672 30 -91-373 ATÓM 6 CG AMET 1 28.626 12.015 5ľ.903 0.542 3 8.19 Anisa about CG AMET 1 7367 4873 227 0 133 912 - 17 6 5 ATÓM 7 SD AMET 1 27.564 11.232 56654 0.542 4 7.19 Anisa 7 SD AMET 1 6146 7957 3827 -2,344 1050 - 13 2 6 ATÓM 8 CE AMET 1 28.129 11.973 55.135 0.542 2 7.10 Anisa 8 CE AMET 1 5030 2111 3155 2345 -1,467 - 9 ATÓM 9 N AASP 2 30.592 14.105 59.425 0268 3 0.20 Anisa 9 N AASP 2 4674 3022 3777 -1210 -782 - 3 8 3 ATÓM 10 CA AASP 2 29.993 15.322 59.963 0268 4.22 Anisa 10 C A AASP 2 5567 2803 4633 -1106 -964 - 5 2 5 ATÓM 11 C AASP 2 28494 15.268 59.655 0268 3 3.34 Anisa 11 C AASP 2 5665 1997 5006 -314 -1457 8 7 7 ATÓM 12 ABOUT AASP 2 28.099 15.650 58551 0268 4.76 Anisa 12 ABOUT AASP 2 6859 5248 4901 -1023 -1582 16 3 1 ATÓM 13 CB AASP 2 30.629 16.528 59281 0268 2 5.98 Anisa 13 CB AASP 2 4424 3085 23 (51 322 -1794 5 8 2 ATÓM 14 CG AASP 2 29.978 17.862 59. 553 0268 38.05 Anisa 14 CG AASP 2 6456 2611 5389 -501 -608 - 1114 ATÓM 15 OD1 AASP 2 28.995 17.937 60318 0268 4 2.35 Anisa 15 OD1 AASP 2 6406 504 9179 873 920 1991 ATÓM 16 OD2 AASP 2 30.449 18.885 58.997 0268 8.59 Anisa 16 OD2 AASP 2 1619 2901 6341 790 -1022 -253 ATÓM 17 N BMET 1 32.709 12.640 58544 0458 9.49 Anisa 17 N BMET 1 4552 2218 4435 -105 1580 4 7 7 ATÓM 18 CA BMET 1 31.874 13.050 57.425 0458 40.62 Anisa 18 CA BMET 1 4228 4809 6395 580 210 1 0 3 ATÓM 19 C BMET 1 30.884 14.113 57.894 0458 8.21 Anisa 19 C BMET 1 5082 3637 5797 282 -909 - 9 15 ATÓM 20 ABOUT BMET 1 30.075 14.599 57.110 0458 4 4.81 Anisa 20 ABOUT BMET 1 8292 3208 5525 2071 -656 - 1 2 ATÓM 21 CB BMET 1 31.131 11.857 56.829 0458 3.14 Anisa 21 CB BMET 1 4866 2613 5114 2013 -122 8 1 8 ATÓM 22 CG BMET 1 29.625 11.840 56.968 0458 4 0.28 Anisa 22 CG BMET 1 4795 5740 476b 230 -751 5 3 ATÓM 23 SD BMET 1 28761 11.495 55422 0458 4.23 Anisa 23 SD BMET 1 5619 3819 3565 2050 -215 2 0 ATÓM 24 CE BMET 1 29.953 12.079 54222 0458 5 4.24 Anisa 24 CE BMET 1 10672 4519 5420 1149 4083 - 2-4 6 3 ATÓM 25 N BASP 2 30.914 14.381 59.194 0732 7.72 Anisa 25 N BASP 2 4433 3914 5984 -1323 -1208 - 1 2 3 4 5 ATÓM 26 CA BASP 2 29.979 15,308 59.811 0732 3 5.78 Anisa 26 CA BASP 2 5412 3387 4794 -1064 -1050 - 7 8 5 ATÓM 27 C BASP 2 28.536 14.886 59.567 0732 9.66 Anisa 27 C BASP 2 4876 1624 4 771 -1561 1 2 1 8 ATÓM 28 ABOUT BASP 2 28181 14.602 58414 0732 3 4.65 Anisa 28 ABOUT BASP 2 4375 3689 5100 65 -1485 2 4 7 ATÓM 29 CB BASP 2 30.195 16.696 59.181 0732 7.39 Anisa 29 CB BASP 2 6632 3351 4222 -1850 869 - 15 18 ATÓM 30 CG BASP 2 29.562 17.730 60.104 0732 3 0.38 Anisa 30 CG BASP 2 3243 3791 4 510 -500 -606 - 119 1 ATÓM 3 1 OD1 BASP 2 28.866 17.247 ó 1 .030 0732 4 8.88

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ANI SOU 31 OD1 BASP 2 627 6 4203 8095 -1203 3,147 - 1 9 0 1 ATÓM 32 OD2 BASP n 29,760 18.945 59.875 0732 3-4 ». 8 5 Anisa 32 OD2 BASP n 2852 3708 6680 -491 443 - 1 4 5 0 ATÓM 33 N THR 3 27.717 14. 789 60606 1,000 5.58 Anisa 33 N THR 3 4586 4123 4811 601 -162S 1516 ATÓM 34 C A THR 3 26303 14.433 60495 1,000 4 0.48 Anisa 34 CA THR 3 4650 4555 6175 371 -911 - 3 8 ATÓM 35 C THR 3 25382 15.647 60611 1,000 3 9.82 Anisa 35 C THR 3 4376 4155 6598 320 -3863 - 5 8 6 ATÓM 36 0 THR 3 24.150 15.556 60.751 1,000 3 3.55 Anisa 36 0 THR 3 4668 3107 4972 357 - 2748 - 5 8 8 ATÓM 37 CB THR 3 25905 13 .450 61613 1,000 3 9.95 Anisa 37 CB THR 3 3787 4004 7387 160 -1209 6 2 ATÓM 38 OG1 THR 3 26.591 13.851 62.817 1,000 6 1.83 Anisa 38 OGL THR 3 10134 5882 7476 -4,164 -3021 2 0 5 1 ATÓM 39 CG2 THR 3 26399 12.052 61278 1,000 59.32 Anisa 39 CG2 THR 3 4613 3971 13955 1114 -3135 -198 ATÓM 40 N THR 4 26036 16.780 60.456 1,000 3 2.55 Anisa 40 N THR 4 4306 4611 3450 377 -2166 -2 17 ATÓM 41 CA THR 4 25.439 18.092 60393 1,000 3 1.22 Anisa 41 CA THR 4 4275 4229 3358 -81 -1180 9 5 ATÓM 42 C THR 4 24.672 18.272 59.090 1,000 3 0.06 Anisa 42 C THR 4 4876 3341 3207 773 - 1156 - 2 0 4 ATÓM 43 0 THR 4 25.195 17.935 58.017 1,000 3 1.64 Anisa 43 0 THR 4 4877 3780 3363 1935 - 1255 - 5 2 ATÓM 44 CB THR 4 26.510 19.208 60407 1,000 3 2.31 Anisa 44 CB THR 4 2320 4762 5194 475 -547 593 ATÓM 45 OGL THR 4 27.324 19091 61578 1,000 3 2.36 Anisa 45 OGL THR 4 3705 3955 4635 -79 - 797 - 3 8 9 ATÓM 46 CG2 THR 4 25.852 20.582 60.458 1,000 7.22 Anisa 46 CG2 THR 4 3728 4174 2443 71,304 - 1 5 1 ATÓM 47 N VAL 5 23.464 18.796 59.211 1,000 2 1.69 Anisa 47 N VAL 5 4041 1985 2215 -543 -657 158 ATÓM 48 CA VAL 5 22.690 19.140 58.024 1,000 2 0.42 Anisa 48 C A VAL 5 3675 1964 2120 -622 -517 103 ATÓM 49 C VAL 5 23.199 20.489 57.499 1,000 1.17 Anisa 49 C VAL 5 2263 1803 2396 -279 -622 8 9 ATÓM 50 0 VAL 5 23.156 21449 58.252 1,000 2 1.10 Anisa 50 0 VAL 5 3662 1885 2472 -389 -656 1 6 ATÓM 51 CB VAL 5 21.204 19.216 58.402 1,000 4.22 Anisa 51 CB VAL 5 3551 2155 3495 -1045 -396 783 ATÓM 52 CG1 VAL 5 20.434 19.700 57.166 1,000 2 0.14 Anisa 52 CG1 VAL 5 3202 1779 2672 -453 10 - 2 ATÓM 53 CG2 VAL 5 20.701 17.867 58.860 1,000 8.58 Anisa 53 CG2 VAL 5 5258 2086 3516 -1226 431 510 ATÓM 54 N PRO 6 23.750 20.542 56.300 1,000 16.95 Anisa 54 N PRO 6 2378 1629 2434 29 -594 301 ATÓM 55 CA PRO 6 24.354 21.793 55857 1,000 16.90 Anisa 55 CA PRO 6 1645 1775 3000 6 -445 303 ATÓM 56 C PRO 6 23.298 22.800 55383 1,000 15.61 Anisa 56 C PRO 6 1477 1766 2687 -192 -437 545 ATÓM 57 0 PRO 6 22.133 22.432 55.201 1,000 15.75 Anisa 57 0 PRO 6 1578 1761 2647 -260 -579 5 5 ATÓM 58 CB PRO 6 25.216 21.375 54.682 1,000 19.85 Anisa 58 CB PRO 6 2320 1752 3468 50 70 18 2 ATÓM 59 CG PRO 6 24.632 20.095 54.187 1,000 4.76 Anisa 59 CG PRO 6 3550 2953 2904 -1186 300-2 8 6 ATÓM 60 CD PRO 6 23.926 19.428 55357 1,000 17.91 Anisa 60 CD PRO 6 1960 1962 2882 -168 -138-4 4 ATÓM 61 N THR 7 23.723 24031 55.156 1,000 14:38 Anisa 61 N THR 7 1518 1567 2378 -158 -616 100

SUBSTTTUTE SHEET (RULE 26)

WO 99 33994

PCT'G 1198'03860

ATÓM 62 CA THR 7 22.907 25.103 54.610 1,000 9.14 Anisa 62 CA THR 7 1625 1554 2174 -255 -5, S ‘2 2 8 ATÓM 63 r * THR 7 23.605 25.684 53.374 1. 000 14.74 ANI SOU 63 C THR 7 1683 1849 2067 -193 -4OS 1 2 1 ATÓM 64 0 THR 7 24.828 25.894 53.423 1,000 15.95 Anisa 64 0 THR 7 1752 2137 2 171 -378 -457 185 ATÓM 6 5 CB THR 7 22 .795 26.248 55637 1,000 15:25 Anisa 65 CB THR 7 1548 1846 2401 -124 5 2 ATÓM 6 6 OG1 THR 7 22.208 25717 56.829 1,000 16.91 Anisa 66 OG1 THR 7 1818 2149 2 <58 -402 -184 4 7 ATÓM 67 CG2 THR 7 21.952 27.387 55. 040 1,000 9.16 Anisa 67 CG2 THR 7 1651 1613 2848 -138 -263 - 2 6 ATÓM 68 N PHE 8 22.830 25.892 52.325 1,000 6.15 Anisa 68 N PHE 8 1966 1618 2137 -411 -55S 230 ATÓM 69 CA PHE 8 23.317 26545 51.136 1,000 14.76 Anisa 69 CA PHE 8 1857 1558 2192 -213 -411 281 ATÓM 70 C PHE 8 22.421 27.728 50.810 1,000 14.94 Anisa 70 C PHE 8 1907 1421 2347 -275 -357 181 ATÓM 71 0 PHE 8 21.198 27.678 50.995 1,000 16:40 Anisa 71 0 PHE 8 1782 1642 2808 -197 -550 3 4 ATÓM 72 CB PHE 8 23.242 25.562 49.948 1,000 16:49 Anisa 72 CB PHE 8 2123 1854 22 37 49 -371-1 ATÓM 73 CG PHE 8 24.225 24.432 50.027 1,000 14.92 Anisa 73 CG PHE 8 1710 1824 213 5 -197 -365 163 ATÓM 74 CD1 PHE 8 23.822 23.227 50.600 1,000 16.78 Anisa 74 CD1 PHE 8 1808 1726 2842 -300 -358 184 ATÓM 75 CD2 PHE 8 25.539 24.558 49.602 1,000 16.67 Anisa 75 CD2 PHE 8 1705 2130 2500 -310 -361 321 ATÓM 76 CE1 PHE 8 24.702 22.183 50742 1,000 16.74 Anisa 76 CE1 PHE 8 2035 1966 2 3 6 9 -4 -99 295 ATÓM 77 CE2 PHE 8 26.420 23.525 49.773 1,000 19:18 Anisa 77 CE2 PHE 8 1398 2153 3736 -408 -631 187 ATÓM 78 CZ PHE 8 26.026 22.336 50.351 1,000 17.90 Anisa 78 CZ PHE 8 1849 2003 2948 -119 -376 2 0 ATÓM 79 N SER 9 23.023 28.776 50.314 1,000 14.82 Anisa 79 N SER 9 2134 1488 2008 -351 -528 310 ATÓM 80 CA SER 9 22.338 29.902 49.715 1,000 15:12 Anisa 80 CA SER 9 2037 1259 2449 -357 -571 134 ATÓM 81 C SER 9 21.977 29607 48.270 1,000 16:19 Anisa 81 C SER 9 2138 1791 2224 -374 -535 547 ATÓM 82 0 SER 9 22.877 29312 47473 1,000 4.17 Anisa 82 0 SER 9 2191 1892 2393 -423 -544 232 ATÓM 83 CB SER 9 23.306 31.113 49.596 1,000 18.74 Anisa 83 CB SER 9 2891 1712 2519 -1012 -478 717 ATÓM 84 OG SER 9 22.738 32.131 48.853 1,000 2 0.82 Anisa 84 OG SER 9 2866 1569 3477 -662 -854 607 ATÓM 85 N LEU 10 20.697 29.674 47.924 1,000 16:46 Anisa 85 N LEU 10 2215 1495 254 2 -228 -740-4 4 8 ATÓM 86 CA LEU 10 20.345 29.401 46.529 1,000 17:55 Anisa 86 CA LEU 10 2263 1856 2551 -582 -693 3 6 ATÓM 87 C LEU 10 21.079 30373 4 5.5 91 1,000 18.84 Anisa 87 C LEU 10 2506 1870 278 4 -596 -830 357 ATÓM 88 0 LEU 10 21.573 30025 44.520 1,000 2 0.19 Anisa 88 0 LEU 10 2705 2263 2704th -524 -663 508 ATÓM 89 CB LEU 10 18.844 29.559 46.227 1,000 18.87 Anisa 89 CB LEU 10 2302 2516 2354 -288 -715 280 ATÓM 90 CG LEU 10 18.355 29.333 44.895 1. 000 18:28 Anisa 90 CG LEU 10 2182 2172 2591 -668 -677 -301 ATÓM 91 CD1 LEU 10 18.708 27.955 44.397 1,000 2.45 Anisa 91 CD1 LEU 10 3418 2024 3089 -308 -537 1 7 ATÓM 92 CD2 LEU 10 16.852 29.603 44.869 1,000 2 1.93

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

I’CT / G 898/03860

Anisa 92 CD2 LEU 1 0 2250 2658 3424 -504 ATÓM 93 N ALA 1 1 21.154 31.63S 46.037 1. 000 Anisa 93 N ALA 11 2862 1780 2977 -595 ATÓM 94 CA ALA 11 21.810 32647 45.202 1. 000 Anisa 94 CA ALA 11 3160 1670 4380 -455 ATÓM 95 C ALA 11 23.285 32309 44.946 1. 000 Anisa 95 C ALA 11 3128 1937 2937 -644 ATÓM 96 ABOUT ALA 11 23 .819 32447 43.829 1,000 Anisa 96 ABOUT ALA 11 3569 3261 3158 -1628 ATÓM 97 CB ALA 11 21.752 33.989 45.953 1,000 Anisa 97 CB ALA 11 3740 1692 3797 -461 ATÓM 98 N GLU 12 23.953 31.844 46.005 1,000 Anisa 98 N GLU 12 2829 1975 3044 -828 ATÓM 99 CA GLU 12 25.354 31463 45.862 1,000 Anisa 99 CA GLU 12 3036 2400 2615 -506 ATÓM 100 C GLU 12 25483 30.277 44.920 1,000 Anisa 100 C GLU 12 3894 2179 2117 -702 ATÓM 101 ABOUT GLU 12 26.375 30.215 44.069 1,000 Anisa 101 ABOUT GLU 12 3463 2917 1971 -1144 ATÓM 102 CB GLU 12 26032 31.170 47.204 1,000 Anisa 102 CB GLU 12 2874 2192 2636 -221 ATÓM 103 CG GLU 12 26.156 32.451 48.032 1,000 Anisa 103 CG GLU 12 2889 2316 2598 -344 ATÓM 104 CD GLU 12 26.787 32.279 49.389 1,000 Anisa 104 CD GLU 12 3146 2542 2619 -1297 ATÓM 105 OE1 GLU 12 27.068 31.149 49803 1,000 Anisa 105 OE1 GLU 12 3642 2681 3169 -1348 ATÓM 106 OE2 GLU 12 26.819 33.305 50.092 1,000 Anisa 106 OE2 GLU 12 5,881 2966 3888 -1119 ATÓM 107 N LEU 13 24.600 29.295 45.060 1,000 Anisa 107 N LEU 13 2567 2345 2275 -351 ATÓM 108 CA LEU 13 24.645 28117 44.174 1,000 Anisa 108 CA LEU 13 2575 2347 2149 -209 ATÓM 109 C LEU 13 24.432 28.566 42.738 1,000 Anisa 109 C LEU 13 3558 2367 2206 -709 ATÓM 110 ABOUT LEU 13 25.102 28.095 41.824 1,000 Anisa 110 ABOUT LEU 13 3827 3216 1981 -823 ATÓM 111 CB LEU 13 23.541 27.137 44.562 1,000 Anisa 111 CB LEU 13 2982 2243 1984 -462 ATÓM 112 CG LEU 13 23.773 26.344 45.860 1,000 Anisa 112 CG LEU 13 2313 2322 2422 -467 ATÓM 113 CD1 LEU 13 22526 25.480 46.070 1,000 Anisa 113 CD1 LEU 13 2769 2266 2845 -789 ATÓM 114 CD2 LEU 13 25.023 25.473 45.858 1,000 Anisa 114 CD2 LEU 13 2709 2229 2585 -244 ATÓM 115 N GLN 14 23.544 29.508 42478 1,000 Anisa 115 N GLN 14 3596 2139 2635 -960 ATÓM 116 CA GLN 14 23.284 29.978 41.104 1,000 Anisa 116 CA GLN 14 3010 3335 2694 -992 ATÓM 117 C GLN 14 24.481 30.712 40.509 1,000 Anisa 117 C GLN 14 3360 3427 2881 -1070 ATÓM 118 ABOUT GLN 14 24.655 30829 39.288 1,000 Anisa 118 0 GLN 14 3836 4657 2922 -1208 ATÓM 119 CB GLN 14 22.064 30906 41.131 1,000 Anisa 119 CB GLN 14 3133 3630 3222 -760 ATÓM 120 CG GLN 14 20.772 30.111 41.355 1,000 Anisa 120 CG GLN 14 3106 2319 3413 -299 ATÓM 121 CD GLN 14 19.586 31.020 41.631 1. 000 Anisa 121 CD GLN 14 3384 2462 3155 -317 ATÓM 122 OE1 GLN 14 19.734 32.104 42.160 1,000 Anisa 122 OE1 GLN 1 4 4973 2619 3175 -183

-1139 7 5 2.0 .., 0 4 -1279 4 7 2 4.24 -979 8 9 1 2 1.06 -1016 4 3 1 6.29 -923 1 13 7 4.29 -216 9 9 6 2 0.65 -930 6 7 4 2 1.19 -715 5 9 8 2 1.56 -206 9 8 8 2 1.98 -488 6 1 8 2 0.27 -624 5 0 1 2 0.54 -516 4 0 6 2 1.86 -612 7 9 9 24.98 -1088 113 4 3 3.52 -2,251 4 6 18.91 -390 3 8 2 18.61 270 4 0 6 2 1.40 -41 5 2 6 2 3.75 -117 1 9 0 18.97 -145 4 4 0 18:57 -362 7 4 5 2 0.74 -142 5 9 4

19.80

-509-1 0 7

2 2.03 -903 3 7 9 2 3.79 -816 6 4 8 5.44 -382 4 8 7 3 0.04 -427 8 9 8 6.28 -863 9 3 8 3.26 -577 5 1 4 2 3.69 - 393 - 1 9 6 8.34 -732 - 4 0 8

SUBSTITUTE SHEET (RULE 26). \\ O 99/33994

PCT GB9SO3S60

ATÓM 123 NE2 GLN 1 -1 16.398 30.513 41.349 1. 000 2 3 5 0 Anisa 123 NE2 GLN 1 4 3O5S 2969 294 1 -3S3 5-1 2 4 S ATÓM 124 N GLN 1 5 25.309 31.243 41.395 1. 000 2 5 ¾ 0 0 Anisa 124 N GLN 1 5 307S 3281 3140 -1159 - 3 9 4 5 7 4 ATÓM 125 CA GLN 1 5 26.530 31.936 43.945 1,000 2 4.05 Anisa 125 CA GLN 15 2947 3560 2 631 -866 - 9 N 6 5 5 ATÓM 126 C GLN 15 27.650 30.920 40.707 1,000 2 6. 0 ó Anisa 126 C GLN 15 3810 3951 213 9 -345 406 668 ATÓM 127 ABOUT GLN 15 28.756 31.284 40302 1,000 3 5. S 5 Anisa 127 ABOUT GLN 15 4294 4851 4 <, 7 6 102 1871 1192 ATÓM 128 CB GLN 15 27.018 32918 42.009 1,000 2 5.90 Anisa 128 CB GLN 15 3055 3037 3548 -1092 -109 364 ATÓM 129 CG GLN 15 26.103 34.092 42.219 1,000 3 1.24 Anisa 129 CG GLN 15 4562 2577 473 1 -806 961 1 0 5 4 ATÓM 130 CD GLN 15 26.503 35.022 43.348 1,000 9.75 Anisa 130 CD GLN 15 9927 2475 10301 -1855 -14 - 1 9 0 3 ATÓM 131 OE1 GLN 15 27.634 35031 43.840 1,000 8 1.81 Anisa 131 OE1 GLN 15 15059 3931 12094 -944 -6272 - 1 8 0 4 ATÓM 132 ΝΞ2 GLN 15 25.539 35.841 43.767 1,000 9 1.46 Anisa 132 NE2 GLN 15 14070 4846 15833 -923 3672 - 4 8 5 1 ATÓM 133 N GLY 16 27.379 29.643 40.969 1,000 2 9.90 Anisa 133 N GLY 16 4634 3820 2907 -239 21 7 8 7 ATÓM 134 C A GLY 16 28.410 28.649 40.699 1,000 8.76 Anisa 134 CA GLY 16 4466 3629 28 33 -709 461 250 ATÓM 135 C GLY 16 29.339 28.473 41.878 1,000 2 7.60 Anisa 135 C GLY 16 3816 3779 2891 -616 913 14 8 5 ATÓM 136 ABOUT GLY 16 30.398 27.867 41.725 1,000 3 1.47 Anisa 136 ABOUT GLY 16 3386 4758 3814 -899 1244 1 0 2 3 ATÓM 137 N LEU 17 28.960 28.898 43.083 1,000 2 6.01 Anisa 137 N LEU 17 3295 3636 2950 -721 162 743 ATÓM 138 CA LEU 17 29.776 28.666 44.257 1,000 23.96 Anisa 138 CA LEU 17 2700 3032 3 372 -601 100 673 ATÓM 139 C LEU 17 29462 27.338 44932 1,000 2 0.31 Anisa 139 C LEU 17 2222 2763 2733 -252 611 261 ATÓM 140 ABOUT LEU 17 28389 26.780 44.789 1,000 23:13 Anisa 140 ABOUT LEU 17 2347 3134 3308 -443 263 859 ATÓM 141 CB LEU 17 29.645 29806 45.286 1,000 2 5.94 Anisa 141 CB LEU 17 2886 2933 4035 -1318 -405 254 ATÓM 142 CG LEU 17 29.962 31.209 44716 1,000 3 1.57 Anisa 142 CG LEU 17 3741 2948 5308 -523 1150 722 ATÓM 143 CD1 LEU 17 29.550 32358 45.615 1,000 3 2.04 Anisa 143 CD1 LEU 17 5221 2887 4066 -1269 278 508 ATÓM 144 CD2 LEU 17 31.458 31278 44.416 1,000 3 8.11 Anisa 144 CD2 LEU 17 3828 5491 5160 -2,315 954 232 ATÓM 145 N HIS 18 30.441 26.822 45.681 1,000 2.49 Anisa 145 N HIS 18 2600 3067 2877 -662 43 4 4 9 ATÓM 146 CA HIS 18 30.289 25.644 46.537 1,000 1.54 Anisa 146 CA HIS 18 2378 2809 299 5 -432 201 313 ATÓM 147 C HIS 18 29.908 24.376 45.790 1,000 2 2.76 Anisa 147 C HIS 18 2256 3245 314 8 -1009 282 114 ATÓM 148 ABOUT HIS 18 29.147 23.565 46.331 1,000 2 2.60 Anisa 148 ABOUT HIS 18 2008 3064 3 516 -629 -166 884 ATÓM 149 CB HIS 18 29.224 25.872 47.618 1,000 2 2.81 Anisa 149 CB HIS 18 2514 2879 3272 -526 450 421 ATÓM 150 CG HIS 18 29.320 27.248 48.217 1,000 2 1.70 Anisa 150 CG HIS 18 2797 3038 2411 -149 38 5 0 3 ATÓM 151 ND1 HIS 18 30438 27.773 48.807 1,000 2 5.01 Anisa 151 ND1 HIS 18 3714 3505 2 2 8 4 -207 -629 149 ATÓM 152 CD2 HIS 18 28.370 28.216 48.269 1. 000 2 4.95 Anisa 152 CD2 HIS 1 8 3244 3278 2 9 5 5 ' 87 544 275 ATÓM 153 CE1 HIS 18 30.197 28.982 49.223 1,000 9.26

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ANISOU 153 CEl HIS 18 4603 3 396 3113 -388 -33 5 2 7 ATÓM 154 ΝΞ2 HIS 18 28.937 29.271 48.919 1. 000 2 1 Anisa 154 ΝΞ2 HIS 18 4582 3137 2632 2,224 3 6 5 ATÓM 155 N GLN 19 30.269 24.270 44.521 1,000 2 2.74 Anisa 155 N GLN 19 2724 3094 2822 -511 -123 4 2 3 ATÓM 156 C A GLN 19 29806 23.113 43 .730 1,000 2 3.85 Anisa 156 CA GLN 19 3129 2668 3263 148 63 8 9 ATÓM 157 C GLN 19 30.271 21.760 44.221 1,000 2.77 Anisa 157 C GLN 19 2532 3026 3095 -502 -574 7 7 8 ATÓM 158 ABOUT GLN 19 29.480 20.801 44.259 1. 000 2 1.99 Anisa 158 ABOUT GLN 19 1869 2911 3574 -187 0 5 5 8 ATÓM 159 CB GLN 19 30.227 23.322 42.276 1,000 7.66 Anisa 159 CB GLN 19 5043 2519 2947 29 -339,458 ATÓM 160 CG GLN 19 29.397 24.333 41.523 1,000 6.21 Anisa 160 CG GLN 19 3289 3163 3508 299 171 4 3 7 ATÓM 161 CD GLN 19 27.917 24.368 41862 1,000 3 2.47 Anisa 161 CD GLN 19 3403 4411 4521 -986 535 6 5 4 ATÓM 162 OE1 GLN 19 27.154 23.604 41.277 1,000 9.69 Anisa 162 OE1 GLN 19 3996 4238 6845 -262 -2770 18 2 9 ATÓM 163 NE2 GLN 19 27.511 25.212 42.811 1,000 42.55 Anisa 163 NE2 GLN 19 3803 6153 6212 82 1944 1 1 ATÓM 164 N ASP 20 31526 21.572 44.631 1,000 22.63 Anisa 164 N ASP 20 2073 3400 3123 -414 94 7 0 8 ATÓM 165 CA ASP 20 31.926 20.292 45225 1,000 2 3.10 Anisa 165 C A ASP 20 1869 3674 3235 83 236704 ATÓM 166 C ASP 20 31.190 20.042 46.546 1,000 0.03 Anisa 166 C ASP 20 1775 2963 2873 -280 -143 4 9 3 ATÓM 167 ABOUT ASP 20 30772 18.899 46.768 1,000 21:48 Anisa 167 ABOUT ASP 20 1429 2884 3848 -311 225 2 2 4 ATÓM 168 CB ASP 20 33.414 20.268 45.521 1,000 27.66 Anisa 168 CB ASP 20 1835 4546 4130 -16 207 8 8 1 ATÓM 169 .CG ASP 20 34.298 20.206 44.291 1,000 39.35 Anisa 169 CG ASP 20 2355 6893 5705 -654 1323 - 19 15 ATÓM 170 OD1 ASP 20 33.870 19.914 43.153 1,000 35.78 Anisa 170 OD1 ASP 20 3152 5452 4992 -741 1508 - 7 9 7 ATÓM 171 OD2 ASP 20 35.508 20.433 44.467 1,000 45.22 Anisa 171 OD2 ASP 20 2201 8705 6277 -589 1088 - 8 7 ATÓM 172 N GLU 21 31.046 21.053 47.404 1,000 1.20 Anisa 172 N GLU 21 1574 2935 3093 -412 -241 3 6 7 ATÓM 173 CA GLU 21 30.323 20.811 48.665 1,000 18.97 Anisa 173 CA GLU 21 1412 2956 2838 -481 -464 1 1 8 ATÓM 174 C GLU 21 28.858 20.448 48.402 1,000 17.84 Anisa 174 C GLU 21 1386 2342 3050 -307 -395 2 3 4 ATÓM 175 ABOUT GLU 21 28.290 19.602 49.054 1,000 18:46 Anisa 175 ABOUT GLU 21 1671 2286 3057 -419 -351 1 1 6 ATÓM 176 CB GLU 21 30.415 22.058 49.563 1,000 0.10 Anisa 176 CB GLU 21 1646 2821 3170 -514 -499 1 2 7 ATÓM 177 CG GLU 21 31.893 22.322 49918 1,000 2 4.11 Anisa 177 CG GLU 21 1682 3568 3912 -766 -326 - 7 11 ATÓM 178 CD GLU 21 32.574 23.380 49.081 1,000 9.70 Anisa 178 CD GLU 21 1330 4241 5713 -752 -666 5 2 1 ATÓM 179 OE1 GLU 21 32.249 23594 47.887 1,000 5.14 Anisa 179 OE1 GLU 21 2623 4054 6677 -1336 -1741 19 7 7 ATÓM 180 OE2 GLU 21 33.483 24.007 49.678 1,000 39.39 Anisa 180 OE2 GLU 21 3681 4425 6860 -2,089 -1618 6 4 7 ATÓM 181 N PHE 22 28.231 21.048 47.395 1,000 17:30 Anisa 181 N PHE 22 1540 2352 2680 -243 -446 - 7 9 ATÓM 182 C A PHE 22 26.851 20.761 47.071 1,000 17:13 Anisa 182 C A PHE 22 1534 2166 2807 -235 -396 3 7 4 ATÓM 183 C PHE 22 26733 19 Dec 329 46.552 1,000 17:41 Anisa 183 C PHE 22 1688 2500 2427 -502 -334 1 0 4

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03S60

ATÓM 1 S4 0 PH E 2 25.867 18.574 4 6,995 1. 000 7 5.8 7 Anisa 184 ABOUT PHE 2 2 1570 2118 2 34 3 -249 -361 131 ATÓM 185 CS ΡΗΞ 2 2 26305 21.840 46.149 1. 000 i W 0 0 Anisa 185 CB PHE 2 2 1747 2754 23 37 70 -178,445 ATÓM 186 CG PHE 22 24.802 21 .729 45.930 1,000 16:38 Anisa 186 CG PHE 22 1763 1748 2714 -90 -326 223 ATÓM 187 CD1 PHE 2 2 23. 934 21.723 47.003 1. 000 18:29 Anisa 187 CD1 PHE 22 1812 2091 3 045 -197 -88 576 ATÓM 188 CD2 PHE 22 24.290 21.720 44.641 1. 000 18.62 Anisa 188 CD2 PHE 22 2106 2079 2 3 90 -143 -623 394 ATÓM 189 CE1 PHE 22 22569 21.727 46.771 1. 000 18.90 Anisa 189 CE1 PHE 22 1826 2086 3271 -198 -133 302 ATÓM 190 CE2 PHE 22 22.911 21.660 44.379 1,000 19:28 Anisa 190 CE2 PHE 22 2189 2023 3114 -242 - 754 - 1 4 4 ATÓM 191 CZ PHE 22 22.059 21.645 45.473 1,000 19:42 Anisa 191 CZ PHE 22 2048 1723 3607 90 -483 -376 ATÓM 192 N ARG 23 27.580 18.971 45 .583 1,000 17.88 Anisa 192 N ARG 23 1647 2437 2709 -168 -218 317 ATÓM 193 CA ARG 23 27.520 17.594 45.079 1,000 19:18 Anisa 193 CA ARG 23 1724 2539 3022 -166 36158 ATÓM 194 C ARG 23 27.767 16.595 46.211 1,000 19:11 Anisa 194 C ARG 23 1279 2461 3518 -173 -113 455 ATÓM 195 ABOUT ARG 23 27.107 15.547 46.229 1,000 18.82 Anisa 195 ABOUT ARG 23 1614 2156 3381 -33 181 - 12 8 ATÓM 196 CB ARG 23 28605 17.351 44.030 1,000 2 2.81 Anisa 196 CB ARG 23 1934 4099 2633 -34 -105 - 3 4 5 ATÓM 197 CG ARG 23 28.248 17.790 42617 1,000 4.82 Anisa 197 CG ARG 23 2601 4078 2752 191 -122-2 0 0 4 ATÓM 198 CD ARG 23 29376 17.272 41685 1,000 9.71 Anisa 198 CD ARG 23 2503 5619 3168 -285 908 704 ATÓM 199 NE ARG 23 30.479 18.206 41.800 1,000 3 0.96 Anisa 199 NE ARG 23 2877 5034 3851 -43 286 297 ATÓM 200 CZ ARG 23 30.549 19.360 41 .148 1,000 9.49 Anisa 200 CZ ARG 23 2612 5063 3 52 9 -225 606 177 ATÓM 201 NH1 ARG 23 29.536 19665 40.328 1,000 9.26 Anisa 201 NH1 ARG 23 3242 4951 2 92 3 -960 331 525 ATÓM 202 NH2 ARG 23 31.629 20092 41.345 1,000 3 2.61 Anisa 202 NH2 ARG 23 2320 5347 4722 -134 519 179 ATÓM 203 N ARG 24 28708 16.851 47.125 1,000 17.80 Anisa 203 N ARG 24 1262 2168 3332 183 38 9 8 ATÓM 204 CA ARG 24 28.930 15.899 48.222 1,000 18.85 Anisa 204 CA ARG 24 1368 2509 3287 69 -162 105 ATÓM 205 C ARG 24 27.701 15.811 49114 1,000 17:51 Anisa 205 C ARG 24 1456 2015 3181 132 -177 243 ATÓM 206 ABOUT ARG 24 27.333 14.733 49.544 1,000 17.93 Anisa 206 ABOUT ARG 24 1851 1965 2997 -16 -402 253 ATÓM 207 CB ARG 24 30.203 16.321 48.991 1,000 19.88 Anisa 207 CB ARG 24 1685 2700 3169 -398 -218 4 4 ATÓM 208 CG ARG 24 31.459 16.053 48.135 1,000 2 9.07 Anisa 208 CG ARG 24 1467 4625 4954 269 203 709 ATÓM 209 CD ARG 24 32.700 16.206 49.016 1,000 4 1.84 Anisa 209 CD ARG 24 1745 7021 7130 -451 -494-9 2 2 ATÓM 210 NE ARG 24 33.690 17.103 48 .464 1,000 5 7.06 Anisa 210 NE ARG 24 4362 9316 8003 -3326 -669-1 1 1 4 1 ATÓM 211 CZ ARG 24 34.032 18327 48.810 1,000 6 0.67 Anisa 211 CZ ARG 24 5961 10369 6723 -4,627 -1324 - 1 5 8 7 ATÓM 212 NH1 ARG 24 33.430 18.980 49. 799 1,000 4 9.70 Anisa 212 NH1 ARG 24 7748 6565 4569 -951 -2185 2226 ATÓM 213 NH2 ARG 24 34. 997 18.971 48. L59 1,000 5 4.12 Anisa 213 NH2 ARG 24 8696 8490 3 3 73 -3780 -2352 1 6 0 6 ATÓM 214 N CYS 25 27.092 16.963 49.370 1,000 15.74

SUBSTTTUTE SHEET (RULE 26)

WO 99'33994

PCT / GB98 / 03860

Anisa 214 N CYS 25 1435 1969 2574 - 16 -393 - 3 3 ATÓM 215 CA CYS 25 25.884 16.921 50 .223 1. 000 16 ,. 3 9 Anisa 215 C Ä CYS 25 1518 1954 2756 -95 -317 - 3 0 0 ATÓM 216 C CYS 25 24.826 16.068 49547 1,000 15.73 Anisa 216 C CYS 2 5 1629 1699 2648 -114 -432 6 6 ATÓM 217 0 CYS 25 24.124 15.262 50.155 1,000 15.89 Anisa 217 0 CYS 25 1453 1801 2783 -88 -469 2 5 2 ATÓM 218 CB CYS 25 25.367 18.362 50.424 1,000 15.93 Anisa 218 CB CYS 25 1644 1779 2629 -49 -261 - 3 0 ATÓM 219 SG CYS 25 23.700 18.417 51.184 1,000 17.82 Anisa 219 SG CYS 25 1742 1825 3202 -122 -33 - 5 5 ATÓM 220 N LEU 26 24.623 16.308 48 .250 1,000 15:25 Anisa 220 N LEU 26 1449 1843 2504 -54 -263 - 14 2 ATÓM 221 CA LEU 26 23.560 15.590 47.534 1,000 15.62 Anisa 221 CA LEU 26 1616 1739 2580 -86 -453 4 8 ATÓM 222 C LEU 26 23.763 14.085 47.621 1,000 15:18 Anisa 222 C LEU 26 1697 1764 2306 -113 -479 6 ATÓM 223 0 LEU 26 22.819 13.345 47.771 1,000 16.96 Anisa 223 0 LEU 26 1797 1725 2920 -234 -6ó4 - 3 0 0 ATÓM 224 CB LEU 26 23.526 16.068 46.066 1,000 16.2 Anisa 224 CB LEU 26 1811 1645 2633 -191 -483 1 2 2 ATÓM 225 CG LEU 26 23.057 17.510 45.864 1,000 15.69 Anisa 225 CG LEU 26 1762 1716 2485 -15 7 9 ATÓM 226 CD1 LEU 26 23.252 17.880 44.405 1,000 17:48 Anisa 226 CD1 LEU 26 1750 2360 2532 -17 -130 4 6 5 ATÓM 227 CD2 LEU 26 21.584 17.680 46.290 1,000 17:11 Anisa 227 CD2 LEU 26 1655 2188 2660 -29 -75 1 6 8 ATÓM 228 N ARG 27 25.027 13.648 47.494 1,000 17:26 Anisa 228 N ARG 27 1870 1818 2871 155 -326 1 4 0 ATÓM 229 CA ARG 27 25.295 12.205 47372 1,000 18.75 Anisa 229 CA ARG 27 2108 1845 3170 270 -955 1 0 2 ATÓM 230 C ARG 27 25.240 11.599 48.744 1,000 17.95 Anisa 230 C ARG 27 1667 1801 3351 159 -897 2 1 9 ATÓM 231 0 ARG 27 24.777 10.454 48.913 1,000 2 0.99 Anisa 231 ABOUT ARG 27 2158 1793 4026 -43 -360 1 6 8 ATÓM 232 CB ARG 27 26.641 12.008 46.670 1,000 2 1.35 Anisa 232 CB ARG 27 2815 2034 3264 622 -377 - 12 9 ATÓM 233 N ASP 28 25.827 12.293 49.723 1,000 16.71 Anisa 233 N ASP 28 1487 2004 2856 178 -328 6 7 ATÓM 234 CA ASP 28 26.034 11.672 51.026 1,000 17:47 Anisa 234 CA ASP 28 1613 2095 2931 107 -301 1 2 7 ATÓM 235 C ASP 28 24.872 11.866 51.990 1,000 17:22 Anisa 235 C ASP 28 1414 2264 2863 223 -447 4 7 1 ATÓM 236 0 ASP 28 24.816 11.081 52.937 1,000 17.62 Anisa 236 ABOUT ASP 28 1932 2139 2624 150 -565 3 2 7 ATÓM 237 CB ASP 28 27.306 12.237 51657 1,000 22:17 Anisa 237 CB ASP 28 1581 3894 2948 -272 -467 5 5 9 ATÓM 238 CG ASP 28 28.590 11.906 50.941 1,000 24.72 Anisa 238 CG ASP 28 1596 3323 4472 236 -288 6 4 8 ATÓM 239 OD1 ASP 28 28.572 10.905 50.199 1,000 27.56 Anisa 239 OD1 ASP 28 2317 3071 5084 808 -284 5 7 2 ATÓM 240 OD2 ASP 28 29.573 12.617 51.251 1,000 32.08 Anisa 240 OD2 ASP 28 1584 4343 6261 -144 -470 4 1 6 ATÓM 241 N LYS 29 24098 12.942 51.821 1,000 15:57 Anisa 241 N LYS 29 1475 1814 2627 5 -302 1 7 8 ATÓM 242 CA LYS 29 23.048 13.305 52778 1,000 15:13 Anisa 242 C A LYS 29 1584 1999 2165 -68 -500 - 9 6 ATÓM 243 C LYS 29 21.686 13,500 52.118 1,000 14:56 Anisa 243 C LYS 29 1496 1352 2686 77 -452 1 0 6 ATÓM 244 ABOUT LYS 29 20.688 12.985 52.635 1,000 16:21 Anisa 244 ABOUT LYS 29 1627 1876 2657 -177 -315 - 5

SUBSTITUTE SHEET (RULE 25)

WO 99/33994

PCT / GB98 / 03860

ATÓM 24 5 C B LYS 2 9 23.431 1-1 .563 5 b. 571 1 0C0 16.09 Anisa 245 CB LYS 2 9 1666 1672 2 77 7 3 - ó ‘ 12 t2 5 ATÓM 246 CG LYS 29 24.776 14.421 54.292 1. 000 17.68 Anisa 246 CG LYS 29 2192 1918 2 c 0 o 7 -1144 141 ATÓM 247 CD LYS 29 25.161 15.647 55.096 1,000 2 0.71 Anisa 247 CD LYS 29 2675 2044 3151 -35 -1517 4 1 ATÓM 248 CE LYS 29 26.498 15331 55.844 1,000 2.24 Anisa 248 CE LYS 29 2203 2714 3535 142 -1369 - 6 8 ATÓM 249 NZ LYS 29 26.955 16.594 56.492 1,000 3 2.67 Anisa 249 NZ LYS 29 3199 3381 583 1 -502 -2086 - 1 2 6 0 ATÓM 250 N GLY 30 21.604 14.198 50.993 1,000 9.14 Anisa 250 N GLY 30 1552 1461 23 4 0 135 -455 - 0 0 0 ATÓM 251 CA GLY 30 20.358 14.373 50.250 1,000 9.14 Anisa 251 CA GLY 30 1428 1561 23 55 92 -342-9 7 ATÓM 252 C GLY 30 19.372 15.284 50.955 1,000 12:30 Anisa 252 C GLY 30 1423 1192 2 05 9 -95 -275 9 4 ATÓM 253 ABOUT GLY 30 18.168 15223 50.696 1,000 14:58 Anisa 253 ABOUT GLY 30 1435 1689 2 415 -476 - 1 2 1 ATÓM 254 N LEU 31 19.884 16.146 51.823 1,000 13.93 Anisa 254 N LEU 31 1472 1479 2343 -182 -248-1 8 1 ATÓM 255 CA LEU 31 19.012 17.114 52.511 1,000 14:44 Anisa 255 C A LEU 31 1534 1457 2 495 -235 -55 - 2 5 6 ATÓM 256 C LEU 31 19.894 18286 52.942 1,000 8.15 Anisa 256 C LEU 31 1411 1535 2784 -177 -326- 3 1 4 ATÓM 257 ABOUT LEU 31 21.113 18.136 53.140 1,000 15.64 Anisa 257 ABOUT LEU 31 1468 1664 2812 -169 -328-6 6 ATÓM 258 CB LEU 31 18.222 16.560 53694 1,000 16.76 Anisa 258 CB LEU 31 2192 1664 2511 -367 128 - 1 2 3 ATÓM 259 CG LEU 31 18.883 16.517 55039 1,000 2 0.16 Anisa 259 CG LEU 31 2435 2485 2739 -289 -141 445 ATÓM 260 CD1 LEU 31 17.977 16.145 56202 1,000 6.49 Anisa 260 CD1 LEU 31 2253 5076 2738 -508 -341 969 ATÓM 261 CD2 LEU 31 20.052 15.526 55.032 1,000 4.73 Anisa 261 CD2 LEU 31 4192 2967 2237 1001 152 6 1 0 ATÓM 262 N PHE 32 19.289 19.462 53.052 1,000 14:11 Anisa 262 N PHE 32 1569 1457 233 5 -231 -179 - 2 0 6 ATÓM 263 CA PHE 32 20.020 20.697 53417 1,000 13:56 Anisa 263 CA PHE 32 1447 1389 2317 -225 -137 1 4 ATÓM 264 C PHE 32 18.976 21.777 53.Ó87 1,000 13.72 Anisa 264 C PHE 32 1411 1439 236'5 -218 -421- 1 4 2 ATÓM 265 ABOUT PHE 32 17.889 21.711 53.118 1,000 15:50 Anisa 265 ABOUT PHE 32 1392 1862 2 63 4 -175 -436 - 3 9 9 ATÓM 266 CB PHE 32 20.958 21.157 52.308 1,000 1.15 Anisa 266 CB PHE 32 1379 2201 212 5 -305 -342 231 ATÓM 267 CG PHE 32 20.381 21.156 50.920 1,000 14.60 Anisa 267 CG PHE 32 1649 1662 2237 -193 -429 118 ATÓM 268 CD1 PHE 32 20.326 19.986 50.148 1,000 14:53 Anisa 268 CD1 PHE 32 1328 1688 2504 -156 -508 1 5 ATÓM 269 CD2 PHE 32 19.831 22.345 50.396 1,000 13.66 Anisa 269 CD2 PHE 32 1320 1678 2191 -179 -309 166 ATÓM 270 CE1 PHE 32 19.742 20.033 48. £ 92 1,000 14:26 Anisa 270 CE1 PHE 32 1507 1655 2256 -346 -270 19 9 ATÓM 271 CE2 PHE 32 19.267 22.348 49.138 1,000 15:49 Anisa 271 CE2 PHE 32 1681 1932 2272 -504 - 1 2 6 ATÓM 272 CZ PHE 32 19.177 21.184 48.385 1,000 15:25 Anisa 272 CZ PHE 32 1979 1700 2117 -185 -295 168 ATÓM 273 N TYR 33 19.376 22.785 54.442 1,000 14:44 Anisa 273 N TYR 33 1813 1302 2372 -237 -496 - 5 0 ATÓM 274 CA TYR 33 18.616 24.023 54 .519 1. 000 14:32 Anisa 274 C A TYR 33 1764 1415 2261 -143 -295-1 1 1 1 ATÓM 275 C TYR 3 3 19.039 24.929 53 .364 1,000 13.70

SUSSTm / TE SHEET

WO 99/33994

PCT / GB98 / 03860

Anisa 275 C TYR 33 1479 1565 2161 -79 -459 - 5 ATÓM 276 0 TYR 33 20.158 24.871 52.859 1. 000 16x28 Anisa 276 0 TYR 33 1370 1524 2912 -190 -420 263 ATÓM 277 CB TYR 33 18874 24.734 55.853 1,000 14:47 Anisa 277 CB TYR 33 1648 1717 2133 -197 -309-1 1 3 1 ATÓM 278 CG TYR 33 18.231 24.046 57.049 1,000 15.71 Anisa 278 C G TYR 33 2131 1537 2302 -339 -109 - 1 6 ATÓM 279 CD1 TYR 33 16.938 24.390 57.453 1,000 17:41 Anisa 279 CD1 TYR 33 2478 1967 2172 -154 246-2 4 9 ATÓM 280 CD2 TYR 33 18.912 23.116 57.799 1,000 19:58 Anisa 280 CD2 TYR 33 2901 2070 2468 144 115 192 ATÓM 281 CE1 TYR 33 16.354 23.758 58542 1,000 2 0.18 Anisa 281 CE1 TYR 33 3138 1948 2581 26,740 - 1 0 2 ATÓM 282 CE2 TYR 33 18.368 22.475 58.900 1,000 2 1.50 Anisa 282 CE2 TYR 33 3571 2480 2118 340 196 122 ATÓM 283 CZ TYR 33 17.081 22.821 59.263 1,000 22.2 Anisa 283 CZ TYR 33 4140 1772 2454 471 1035 - 1 0 4 ATÓM 284 OH TYR 33 16.541 22.194 60355 1,000 9.55 Anisa 284 OH TYR 33 5088 2809 3329 377 1512 728 ATÓM 285 N LEU 34 18.076 25.709 52.878 1,000 14:28 Anisa 285 N LEU 34 1496 1533 2396 -80 -517 - 1 7 ATÓM 286 CA LEU 34 18.278 26.620 51.756 1,000 2.15 Anisa 286 CA LEU 34 1830 1452 2425 -126 -580 2 0 ATÓM 287 C LEU 34 17.871 28.039 52.151 1,000 14:46 Anisa 287 C LEU 34 1703 ₄ 1575 2217 -146 -241-7 ATÓM 288 0 LEU 34 16.716 28.289 52.492 1,000 16.95 Anisa 288 0 LEU 34 1663 1852 2923 -75 -186 - 6 4 ATÓM 289 CB LEU 34 17.389 26.127 50.598 1,000 16:54 Anisa 289 CB LEU 34 2355 1485 2444 -212 -749 2 5 ATÓM 290 CG LEU 34 17.633 26.800 49249 1,000 15.65 Anisa 290 CG LEU 34 2010 1567 2371 -7 -633-6 3 ATÓM 291 CD1 LEU 34 18.977 26.422 48.664 1,000 2 0.14 Anisa 291 CD1 LEU 34 1919 2018 3717 -225 -171 260 ATÓM 292 CD2 LEU 34 16.490 26.535 48.291 1,000 17:29 Anisa 292 CD2 LEU 34 2152 1824 2592 -425 -818 2 14 ATÓM 293 N THR 35 18.842 28.944 52065 1,000 15:48 Anisa 293 N THR 35 1817 1532 2534 -230 -200 1 3 ATÓM 294 CA THR 35 18.587 30.362 52.324 1,000 2.17 Anisa 294 CA THR 35 2149 1537 2781 -206 -827-1 9 6 ATÓM 295 C THR 35 18.491 31.127 51.010 1,000 4.17 Anisa 295 C THR 35 1895 1693 2887 -149 -882-4 4 4 ATÓM 296 0 THR ' 35 18765 30.572 49.938 1,000 1.17 Anisa 296 0 THR 35 1880 1692 2893 -262 -458 144 ATÓM 297 CB THR 35 19.772 30.917 53.180 1,000 17.79 Anisa 297 CB THR 35 2018 1942 2800 -87 - 854 - 2 0 0 ATÓM 298 OG1 THR 35 20.986 30.673 52474 1,000 2 1.10 Anisa 298 OG1 THR 35 2110 2035 3873 -253 -364 - 4 0 1 ATÓM 299 CG2 THR 35 19.847 30.331 54.567 1,000 2 0.44 Anisa 299 CG2 THR 35 2600 2194 2971 228 -1112 5 9 ATÓM 300 N ASP 36 18.186 32.407 51.059 1,000 18.62 Anisa 300 N ASP 36 2287 1747 3040 -187 -316 149 ATÓM 301 CA ASP 36 18.240 33.300 49.884 1,000 2 0.75 Anisa 301 CA ASP 36 2678 1722 3483 -632 -507 3 7 4 ATÓM 302 C ASP 36 17.474 32.711 48.703 1,000 2 0.05 Anisa 302 C ASP 36 2104 1929 3586 198 -927 4 8 9 ATÓM 303 0 ASP 36 17.929 32.685 47.540 1,000 2 1.06 Anisa 303 0 ASP 36 2593 1749 3662 -496 -756 131 ATÓM 304 CB ASP 36 19703 33.561 49.500 1,000 2.21 Anisa 304 CB ASP 36 2666 2366 3406 -876 -755 807 ATÓM 305 CG ASP 36 20.588 34.192 50.551 1,000 2 3.05 Anisa 305 CG ASP 36 2537 1818 4402 -175 - 832 - 2 0 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994 l'CT'GB9S'03S60

ATÓM 306 OD1 ASP 3 6 20.06 3 4.8 N 6 51457 1. 000 2 ó. 1 ó Anisa 30o OD1 ASP 3 6 29s1 2100 4860 378 -777-3 g i ATÓM 307 OD2 ASP 36 21.824 33.982 50.528 1. 000 4.87 Anisa 307 OD2 ASP 36 2532 1994 4924 -49 -950-6 6 2 8 ATÓM 308 N CYS 37 16.282 32196 48. 971 1,000 2 0.25 Anisa 30S N CYS 37 2135 1711 3849 118 -638 - 2 5 3 ATÓM 309 C A CYS 37 15.463 31.587 4 7.902 1,000 2 0.28 Anisa 309 CA CYS 37 2390 1478 3 33 9 136 -799- 1 3 8 ATÓM 310 C CYS 37 14.078 32.183 47.818 1,000 19.90 Anisa 310 C CYS 37 2374 1724 3 463 214 -711-7 4 ATÓM 311 ABOUT CYS 37 13.176 31.629 4. 15 6 1. 000 2.75 Anisa 311 ABOUT CYS 37 2569 1984 4091 -12 -1108 1 5 ATÓM 312 CB CYS 37 15.359 30061 48.083 1,000 2.21 Anisa 312 CB CYS 37 2739 1454 4247 194 -477 - 1 ATÓM 313 SG CYS 37 14,500 29.595 4S.596 1,000 2.84 Anisa 313 SG CYS 37 2854 1884 3942 -203 -922 141 ATÓM 314 N GLY 38 13.855 33.390 48.314 1,000 2 0.85 Anisa 314 N GLY 38 2353 1638 3933 217 -375-4 4 2 ATÓM 315 CA GLY 38 12.570 34044 48.194 1,000 2 3.42 Anisa 315 C A GLY 38 2233 1874 4790 255 -292 165 ATÓM 316 C GLY 38 11.534 33619 49.217 1,000 3.29 Anisa 316 C GLY 38 2577 2045 4228 113 -136 - 6 0 0 ATÓM 317 0 GLY 38 10.400 34.091 49.129 1,000 5.58 Anisa 317 0 GLY 38 2529 3424 3765 214 - 96 - 2 6 4 ATÓM 318 N LEU 39 11.894 32.836 50.237 1,000 2 4.55 Anisa 318 N LEU 39 2310 2980 4037 119 -46- 3 6 4 ATÓM 319 CA LEU 39 10.938 32.331 51195 1,000 4.44 Anisa 319 CA LEU 39 2637 2964 36134 -105 175-9 4 6 ATÓM 320 C LEU 39 11.107 32.885 52.593 1,000 5.41 Anisa 320 C LEU 39 5341 4215 3898 -796 165-143 5 ATÓM 321 0 LEU 39 11.784 32.313 53441 1,000 4 3.41 Anisa 321 0 LEU 39 7338 4986 4171 -2639 -1333 - 3 0 4 ATÓM 322 CB LEU 39 10.850 30.810 51.206 1,000 6.48 Anisa 322 CB LEU 39 4244 2940 2879 49 -70 - 2 6 1 ATÓM 323 CG LEU 39 10.404 30.097 49.921 1,000 3 0.21 Anisa 323 CG LEU 39 4834 2452 4195 258 -1618 -474 ATÓM 324 CD1 LEU 39 10.683 28.595 49.972 1,000 4.78 Anisa 324 CD1 LEU 39 3351 2597 3468 424 -707-1 1 1 8 ATÓM 325 CD2 LEU 39 8.940 30.407 49.640 1,000 2 7.50 Anisa 325 CD2 LEU 39 4828 2118 3503 860 -860- 3 2 3 ATÓM 326 N THR 40 10.365 33.957 52.882 1,000 5.58 Anisa 326 N THR 40 7392 4849 5077 -520 2852 - 1 9 9 4 ATÓM 327 CA THR 40 10.610 34661 54136 1,000 3 2.50 Anisa 327 CA THR 40 4224 3732 4393 999 962 - 5 5 8 ATÓM 328 C THR 40 9.700 34.177 55.248 1,000 2 9.68 Anisa 328 C THR 40 3175 4204 3898 -116 294 - 1 6 4 0 ATÓM 329 0 THR 40 8653 33556 55031 1,000 9.75 Anisa 329 0 THR 40 3930 5847 5326 -1079 -301 - 1 5 6 3 ATÓM 330 CB THR 40 10641 36.183 53.997 1,000 6.31 Anisa 330 CB THR 40 10586 3758 7052 -1417 1006-9 9 2 ATÓM 331 OG1 THR 40 11.545 36.606 52.946 1,000 8.39 Anisa 331 OG1 THR 40 7379 3900 14707 -1978 3617 - 2 5 6 ATÓM 332 CG2 THR 40 11.214 36.837 55.256 1,000 7 0.22 Anisa 332 CG2 THR 40 8265 5228 13113 8 1389 -4421 - 3 2 4 1 ATÓM 333 N ASP 41 10.191 34.302 56.486 1,000 3.20 Anisa 333 N ASP 41 3580 5223 3810 -203 307-1 7 7 9 ATÓM 334 CA ASP 4 1 9329 33943 5 7. (513 1,000 2 7.51 Anisa 334 CA ASP 41 2705 3858 3891 9 1 -254 - 1 0 6 1 ATÓM 335 C ASP 4 1 8. 107 34861 57.660 1. 000 3 3.43 Anisa 335 C ASP 4 1 3131 3064 65 0 « 3 2 545 - 1 3 0 8 ATÓM 336 0 ASP 4 1 7.034 34.469 58101 1. 000 3 0 7 7

SUBSITTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ANI ARE 3 36 ABOUT ASP 4 1 2690 3223 5774 ATÓM 337 CB ASP 4 1 10.113 34135 58 .915 Anisa 337 CB ASP 4 1 4853 4026 3852 ATÓM 338 CG ASP 41 9453 33.351 60039 Anisa 338 CG ASP 4 1 3324 5291 4065 ATÓM 339 OD1 ASP 41 9.152 32.164 59 .780 Anisa 339 OD1 ASP 4 1 4040 4681 4557 ATÓM 340 OD2 ASP 41 9395 33904 61161 Anisa 340 OD2 ASP 41 18972 10427 3567 ATÓM 341 N THR 42 8272 36.089 57.205 Anisa 341 N THR 42 3217 3695 5516 ATÓM 342 C A THR 42 7198 37.074 57 .221 Anisa 342 CA THR 42 4747 4161 5711 ATÓM 343 C THR 42 6005 36.640 56.375 Anisa 343 C THR 42 3333 4044 6237 ATÓM 344 ABOUT THR 42 4,877 36.606 56.900 Anisa 344 ABOUT THR 42 4048 3603 7128 ATÓM 345 CB THR 42 7.751 38.449 56.815 Anisa 345 CB THR 42 4526 3763 5788 ATÓM 346 OG1 THR 42 8.831 38.301 55.889 Anisa 346 OG1 THR 42 16381 13757 7127 ATÓM 347 CG2 THR 42 8,358 39.113 58047 Anisa 347 CG2 THR 42 6097 3613 3997 ATÓM 348 N GLU 43 6259 36.184 55.173 Anisa 348 N GLU 43 4208 3312 5642 ATÓM 349 CA GLU 43 5391 35.557 54.192 Anisa 349 CA GLU 43 3527 2886 6120 ATÓM 350 C GLU 43 4,701 34.300 54.713 Anisa 350 C GLU 43 3454 4151 8229 ATÓM 351 ABOUT GLU 43 3,484 34.124 54.605 Anisa 351 ABOUT GLU 43 3375 4041 7222 ATÓM 352 • CB GLU 43 6278 35.074 53-026 Anisa 352 CB GLU 43 5991 4098 6901 ATÓM 353 CG GLU 43 6658 36.125 52.003 Anisa 353 CG GLU 43 5931 6417 7949 ATÓM 354 CD GLU 43 7.838 36976 52.429 Anisa 354 CD GLU 43 4087 7601 7467 ATÓM 355 OE1 GLU 43 8.024 37.112 53.661 Anisa 355 OE1 GLU 43 7237 7592 7757 ATÓM 356 OE2 GLU 43 8.555 37.476 51.531 Anisa 356 OE2 GLU 43 11550 6344 9207 ATÓM 357 N LEU 44 5511 33.373 55.224 Anisa 357 N LEU 44 2837 2924 4802 ATÓM 358 CA LEU 44 4926 32.222 55.902 Anisa 358 CA LEU 44 2207 3379 5009 ATÓM 359 C LEU 44 3.886 32.670 56934 Anisa 359 C LEU 44 1930 4771 6333 ATÓM 360 ABOUT LEU 44 2,781 32.159 56.924 Anisa 360 ABOUT LEU 44 2046 5235 5390 ATÓM 361 CB LEU 44 5.999 31394 56587 Anisa 361 CB LEU 44 2781 3494 3070 ATÓM 362 CG LEU 44 5.592 30.147 57.343 Anisa 362 CG LEU 44 2414 5135 ' 4517 ATÓM 363 CD1 LEU 44 4563 29.328 56.575 Anisa 363 CD1 LEU 44 5860 7081 5188 ATÓM 364 CD2 LEU 44 6793 29259 57.653 Anisa 364 CD2 LEU 44 6294 3688 9608 ATÓM 365 N LYS 45 4212 33.712 57694 Anisa 365 N LYS 45 2865 6802 6256 ATÓM 366 C A LYS 45 3 .369 34.195 58.773 Anisa 366 CA LYS 4 5 4768 5427 6639

141 - 13 9 - 9 6 9 1. 000 3 3.51 -1222 -698-9 3 8 1,000 3 3.37 -739 -501-5 5 7 1 1,000 3 4.95 -380 824-9 2 1,000 6.76 -10425 588 1 8 5 8 1,000 3 2.71 9 -58-5 5 8 6 1,000 8.48 1067 -861-6 6 0 0 1,000 3 5.83 1136 157-1 1 1 6 2 1,000 3 8.90 1186 1058 1 2 2 4 1,000 3 7.05 1021 -678 - 1 5 3 2 1,000 9 8.08 -3,208 7500 - 2 3 1 7 1,000 6.08 886 -1119 269 1,000 34.64 656 -275 - 6 9 8 1,000 32.98 1199 - 883 - 1 5 2 1,000 4 1.67 225 -1743 953 1,000 38.53 589 -1417 -578 1,000 44.72 28 137 - 2 1 3 6 1,000 5 3.42 -993 1540 - 1 2 3 4 1,000 5 0.41 -439 2486-172 5 1,000 5 9.44 -1284 1632 - 1 2 3 4 1,000 7 1.33 -4,131 6266 - 4 6 4 5 1,000 27.80 -55 -626 - 2 7 1,000 7.88 241 813 -3 82 1,000 3 4.30 -537 776 - 2 7 2 9 1,000 3 3.35 -840 706 - 2 3 9 6 1,000 4.59 81,940 - 7 4 1,000 31.76 -845 790 1 2 1 7 1,000 4 7.71 -3,576 3333 - 2 1. 000 5 1.56 1956 2241 1 3 8 2 1,000 4 1.91 -1455 383 - 3 5 3 6 1. 000 4.31 74 836 - 2 9 8 5

SUBSTITUTE SHEET (RULE 26)

W Ο 90.33994

PCT / GB98'03860

ATÓM 367 C LYS • 1 5 1. 9S 1 34. 5S2 53.278 1. 000 3 3.5 AKľSOU 367 C LYS 4 5 4535 344 5 66S1 -245 12 * 2 · ·! -28 ^ 0 ATÓM 368 0 LYS 45 0.984 34.238 53902 1,000 3 9.93 Anisa 368 0 LYS 4 5 4857 3594 6720 262 1533 - 2 3 3 6 ATÓM 369 CB LYS 45 4038 35.400 59447 1. 000 5 0.20 Anisa 369 CB LYS 45 4944 5561 8569 1081 -447-3980 ATÓM 370 CG LYS 45 3082 36.546 5 9. 706 1,000 5 3.07 Anisa 370 CG LYS 45 3548 6321 13296 1148 -2094 -4809 ATÓM 371 CD LYS 45 3.714 37.922 59622 1,000 5 8.29 Anisa 371 CD LYS 45 4723 5694 117 3 0 1422 -3745 -5024 ATÓM 372 CE LYS 45 3. 199 38.793 60761 1,000 5.33 Anisa 372 CE LYS 45 6294 6898 116 2 9 1072 -3430 -5603 ATÓM 373 N2 LYS 45 1.713 38.779 60852 1,000 7 3.75 Anisa 373 NZ LYS 45 6392 9216 12412 -718 -1071-7 4 3 6 ATÓM 374 N SER 4 6 1973 35.341 57193 1,000 6.94 Anisa 374 N SER 46 4074 3478 6484 -956 1068 - 2 9 ATÓM 375 CA SER 4 6 0743 35.856 56.607 1,000 7.61 Anisa 375 CA SER 46 3983 3417 6892 -1335 990 - 2 3 3 5 ATÓM 376 C SER 46 -0,137 34.702 56.137 1,000 3 4.45 Anisa 376 C SER 46 3430 3057 6602 -1104 1656 - 1 2 3 4 ATÓM 377 0 SER 46 -1,337 34.625 56.449 1,000 2 9.50 Anisa 377 0 SER 46 3195 2789 5224 -587 1093 - 1 2 0 5 ATÓM 378 CB SER 46 1.160 36.726 55419 1,000 4 0.36 Anisa 378 CB SER 46 4102 3809 74.25 -2,099 617 -1930 ATÓM 379 OG SER 46 0.018 37.017 54.630 1,000 4 3.38 Anisa 379 OG SER 46 5005 3431 804 8 -1261 53 -1863 ATÓM 380 N ALA 47 0493 33.808 55 .361 1,000 2 9.82 Anisa 380 N ALA 47 3246 2173 59S.0 -18 809 -1228 ATÓM 381 CA ALA 47 -0.208 32.623 54.879 1,000 2 5.84 Anisa 381 C A ALA 47 3566 2106 4148 7,630 - 8 9 1 ATÓM 382 C ALA 47 -0,722 31.792 56.058 1,000 25.02 Anisa 382 C ALA 47 2591 2344 4572 481 280 - 2 7 0 ATÓM 383 0 ALA 47 -1,888 31.381 56.063 1,000 23:19 Anisa 383 0 ALA 47 2850 2366 3597 129 318–1119 ATÓM 384 CB ALA 47 0615 31791 53.912 1,000 6.76 Anisa 384 CB ALA 47 2892 2764 4511 270 351-113 4 ATÓM 385 N LYS 48 0132 31.529 57.041 1,000 2 4.64 Anisa 385 N LYS 48 3107 2076 4178 130 -57 -1085 ATÓM 386 CA LYS 48 -0.186 30.712 58202 1,000 2 5.83 Anisa 386 CA LYS 48 3545 2979 3291 -16 30 - 1416 ATÓM 387 C LYS 48 -1,337 31.339 59.003 1,000 8.58 Anisa 387 C LYS 48 3373 3344 4144 -354 129 - 2 0 4 0 ATÓM 388 0 LYS 48 -2,310 30.694 59.396 1,000 27.04 Anisa 388 0 LYS 48 3849 2793 3633 312 416 - 6 3 4 ATÓM 389 CB LYS 48 1,035 30.654 59149 1,000 2 8.95 Anisa 389 CB LYS 48 3507 3294 4200 -274 -257-7 3 8 ATÓM 390 CG LYS 48 0.775 29.694 60.313 1,000 3 2.96 Anisa 390 CG LYS 48 4412 3214 48 97 113 -543 - 1 5 7 ATÓM 391 CD LYS 48 1.418 30.222 61.570 1,000 3 9.92 Anisa 391 CD LYS 48 5828 4616 4724 705 -1278 - 3 9 ATÓM 392 CE LYS 48 1,217 29.320 62769 1,000 3 3.67 Anisa 392 CE LYS 48 3973 4020 4799 1402 - 205 - 3 5 6 ATÓM 393 NZ LYS 48 0731 30.100 63946 1,000 8.33 Anisa 393 NZ LYS 48 4516 5230 4816 916 -1039 - 1 5 ATÓM 394 N ASP 49 -1,253 32.656 59.255 1,000 2 3.78 Anisa 394 N ASP 49 2796 3136 3104 78 -459 - 1 5 8 8 ATÓM 395 CA ASP 49 -2,298 33326 60006 1,000 2 4.05 Anisa 395 C A ASP 49 2826 2913 3398 -291 366 - 1 0 3 4 ATÓM 396 C ASP 49 -3,679 33. 181 59.366 1,000 2 4.45 Anisa 396 C ASP 49 2721 3 270 3 300 -220 5 5 5 - 2 3 4 5 ZiTOM 397 0 ASP 4 9 -4,637 32.951 60082 1. 000 2 7.10

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98O3860

Anisa 397 ABOUT ASP 49 2863 3177 4257 -368 1004 - 1 2 3 4 ATÓM 398 CB ASP 49 -2,034 34. 824 60167 1. 000 3 G> 3 4 Anisa 398 C3 ASP 49 3695 3210 4623 -559 713 - 2 1 7 7 ATÓM 399 CG ASP 49 -0,924 35.181 61128 1,000 3 7.18 Anisa 399 CG ASP 49 5259 4057 4810 -1,109 -211 - 2 0 0 6 ATÓM 400 OD1 ASP 49 -0,556 34.266 61904 1. 000 3 3.36 Anisa 400 OD1 ASP 49 3717 4549 4408 -737 890 - 1 7 2 7 ATÓM 401 OD2 ASP 49 -0,525 36.375 61087 1. 000 8.45 Anisa 401 OD2 ASP 49 7960 3575 6875 -927 -2887 - 2 3 0 9 ATÓM 402 N LEU 50 -3,788 33.402 58.059 1. 000 2 4.46 Anisa 402 N LEU 50 3114 2668 3513 374 200-1 1 2 9 8 ATÓM 403 CA LEU 50 -5,123 33. 344 57.471 1,000 2 2.92 Anisa 403 CA LEU 50 2949 2145 3614 161 396 - 5 6 2 ATÓM 404 C LEU 50 -5,679 31937 57.328 1,000 2 1.79 Anisa 404 C LEU 50 3345 2197 2737 33 415 - 5 5 6 ATÓM 405 0 LEU 50 -6,878 31.741 57.475 1,000 2 4.96 Anisa 405 0 LEU 50 3463 2502 3517 -276 767 - 1 1 8 1 ATÓM 406 CB LEU 50 -5,254 34137 56.194 1,000 2.13 Anisa 406 CB LEU 50 3127 2016 3266 -103 525 - 7 5 7 ATÓM 407 CG LEU 50 -6 .661 34.578 55807 1,000 8.87 Anisa 407 CG LEU 50 3549 3538 3881 961 825 208 ATÓM 408 CD1 LEU 50 -7,389 35.082 57.049 1,000 5 2.72 Anisa 408 CD1 LEU 50 4567 8556 6907 940 2929 - 1 9 3 7 ATÓM 409 CD2 LEU 50 -6,644 35.642 54.723 1,000 4 1.07 Anisa 409 CD2 LEU 50 6971 3395 5240 -1005 -2258 857 ATÓM 410 N VAL 51 -4,801 30.956 57.138 1,000 2 1.78 Anisa 410 N VAL 51 3345 2052 2877 -160 216-8 6 0 ATÓM 411 CA VAL 51 -5,293 29.580 57.118 1,000 19:40 Anisa 411 CA VAL 51 2631 2056 2683 -12 173 - 3 0 4 ATÓM 412 C VAL 51 -5,631 29.135 58.533 1,000 5.25 Anisa 412 C VAL 51 4453 2656 2485 -753 588 - 9 5 5 ATÓM 413 0 VAL 51 -6,652 28454 58.725 1,000 2 5.07 Anisa 413 0 VAL 51 4555 2176 2795 -484 1186 - 8 2 7 ATÓM 414 CB VAL 51 -4,377 28.589 56.396 1,000 18.78 Anisa 414 CB VAL 51 2729 1786 2620 -72 171 -313 ATÓM 415 CG1 VAL 51 -3,152 28238 57.231 1,000 20:42 Anisa 415 CG1 VAL 51 3002 1841 2918 295 -13 -480 ATÓM 416 CG2 VAL 51 -5,147 27.306 56021 1,000 4.10 Anisa 416 CG2 VAL 51 3112 2337 3708 -511 355-8 4 6 ATÓM 417 N ILE 52 -4,836 29,500 59.534 1,000 5.23 Anisa 417 N ILE 52 4514 2471 2603 388 76-8 7 4 ATÓM 418 CA ILE 52 -5.205 29.114 60921 1,000 4.38 Anisa 418 CA ILE 52 3488 3010 2765 248 19 - 5 0 8 ATÓM 419 C ILE 52 -6,498 29771 61355 1,000 4.20 Anisa 419 C ILE 52 3026 2482 3687 -354 115 - 6 4 8 ATÓM 420 0 ILE 52 -7,328 29182 62071 1,000 7.73 Anisa 420 0 ILE 52 3735 2812 3989 -198 613 - 3 3 4 ATÓM 421 CB ILE 52 -4,016 29.427 61829 1,000 2 7.59 Anisa 421 CB ILE 52 3321 4347 2815 590 0 - 7 8 4 ATÓM 422 CG1 ILE 52 -2,853 28.439 61510 1,000 3 1.45 Anisa 422 CG1 ILE 52 3278 5248 3425 741 363 - 1 2 7 8 ATÓM 423 CG2 ILE 52 -4,293 29312 63317 1,000 3 3.62 Anisa 423 CG2 ILE 52 3827 6199 2750 881 150-1 4 5 4 ATÓM 424 CD1 ILE 52 -1,930 28.351 62710 1,000 6.22 Anisa 424 CD1 ILE 52 3956 5082 4722 979 -601 - 2 4 4 ATÓM 425 N ASP 53 -6,771 30.992 60913 1. 000 2 4.56 Anisa 425 N ASP 53 3479 2878 2974 165 608 - 4 2 6 ATÓM 426 CA ASP 53 -8,051 31.646 61278 1. 000 2 3.50 Anisa 426 CA ASP 53 3242 2942 2745 - 5 355 - 6 7 7 ATÓM 427 C ASP 53 -9,201 30929 60594 1,000 6.34 Anisa 427 C ASP 53 3462 2986 3561 -435 612 - 1 0 6 3

SUBSTmiTE SHEET (RULE 26) \ WO 99/33994

PCT / GB9S'03860

ATÓM 428 ABOUT AS? 5 3 - 27 · -10.342 30.83Ó 61,051 1,000 1,000 9.73 Anisa 428 ABOUT ASP 5 3 3468 3085 474 3 -436 9 3-8 ·· - 114 2 ATÓM 429 CB ASP 5 3 -7,964 33.084 60772 1. 000 3 3.83 Anisa 4 2 9 CB ASP 53 3800 2322 6730 - 9 2 1806 - 9 3 3 ATÓM 430 CG ASP 53 -9,308 33.758 60583 1. 000 3 2.05 Anisa 430 CG ASP 53 4652 2412 5113 172 -302 - 113 3 ATÓM 431 OD1 ASP 53 -9,653 34.524 61486 1. 000 4 3.68 Anisa 431 OD1 ASP 53 3661 4686 824 8 150 13 79 - 3 12 0 ATÓM 432 OD2 ASP 53 -9,950 33556 59532 1,000 5 1.30 Anisa 432 OD2 ASP 53 8386 6074 5033 -2062 -1738 9 2 2 ATÓM 433 N PHE 54 -8,933 30.376 59413 1,000 5.39 Anisa 433 N PHE 54 3372 2640 3 63 7 72 71 - 1 1 6 7 ATÓM 434 CA PHE 54 -9,917 29.557 58704 1,000 4.10 Anisa 434 CA PHE 54 3015 3264 2676 -366 263 - S 3 9 ATÓM 435 C PHE 54 -10,180 28.259 59456 1,000 2 4.00 Zinis 435 C PHE 54 3264 3174 2680 -365 459 - 6 8 8 ATÓM 436 ABOUT PHE 54 -11,333 27.893 59.686 1,000 2 S. 1 9 Anisa 436 ABOUT PHE 54 3551 3246 3914 -549 1305 - 113 0 ATÓM 437 CB PHE 54 -9,465 29.273 57.263 1,000 2 3.62 Anisa 437 CB PHE 54 3241 2955 2779 -249 218 - 4 3 4 ATÓM 438 CG PHE 54 -10,522 28.499 56.461 1,000 7.62 Anisa 438 CG PHE 54 4712 2945 2838 -694 -636 1 4 ATÓM 439 CD1 PHE 54 -11,729 29.078 56.087 1,000 3 1.38 Anisa 439 CD1 PHE 54 3613 4658 3654 -951 -262 - 6 2 1 ATÓM 440 CD2 PHE 54 -10,283 27.210 56.033 1,000 3 0.92 Anisa 440 CD2 PHE 54 5782 3589 2 3 77 -831 293 - 8 4 4 ATÓM 441 CE1 PHE 54 -12,653 28406 55.307 1,000 4.29 Anisa 441 CE1 PHE 54 5504 5404 5919 -3,066 -2,057 117 8 ATÓM 442 CE2 PHE 54 -11,228 26.503 55.306 1,000 3 8.69 Anisa 442 CE2 PHE 54 7997 4412 2289 -2,803 155 - 3 8 7 ATÓM 443 CZ PHE 54 -12,424 27.092 54.927 1,000 4 2.33 Anisa 443 CZ PHE 54 5992 6305 3787 -4,256 54 - 4 5 6 ATÓM 444 N PHE 55 -9,126 27.558 59.870 1,000 2 5.87 Anisa 444 N PHE 55 3787 2768 3276 -85 431 - 8 3 9 ATÓM 445 CA PHE 55 -9 .195 26.310 60.625 1,000 2 5.69 Anisa 445 C A PHE 55 3567 3042 3151 68,763 - 7 1 1 ATÓM 446 C PHE 55 -9 .929 26.484 61944 1,000 7.69 Anisa 446 C PHE 55 3357 3961 3205 181 703 - 7 19 ATÓM 447 0 PHE 55 -10,745 25.670 62373 1,000 3 0.08 Anisa 447 0 PHE 55 4046 4165 3217 142 878 - 12 7 ATÓM 448 CB PHE 55 -7,759 25.873 60932 1,000 5.48 Anisa 448 CB PHE 55 3556 3159 2964 117 835 - 6 3 8 ATÓM 449 CG PHE 55 -7,019 25.242 59762 1,000 6.31 Anisa 449 CG PHE 55 3437 3039 3522 -468 1068 - 115 6 ATÓM 450 CD1 PHE 55 -7,611 24.820 58.590 1,000 27.09 Anisa 450 CD1 PHE 55 3553 3895 2845 -1018 1404 - 6 5 8 ATÓM 451 CD2 PHE 55 -5,651 25.031 59.935 1,000 3 1.68 Anisa 451 CD2 PHE 55 3244 4185 4609 -726 1123 - 2 2 2 1 ATÓM 452 CE1 PHE 55 -6,878 24.150 57.521 1,000 2 3.89 Anisa 452 CE1 PHE 55 3472 2525 3079 -58 551 - 5 4 7 ATÓM 453 CE2 PHE 55 -4,904 24.433 58.950 1,000 3 1.74 Anisa 453 CE2 PHE 55 3487 4387 4186 226 337 - 2 3 0 4 ATÓM 454 CZ PHE 55 -5,514 24.004 57.770 1,000 4.23 Anisa 454 CZ PHE 55 3706 2187 3312 414 -22 - 4 16 ATÓM 455 N GLU 56 -9,633 27.581 62. (529 1,000 3 0.39 Anisa 455 N GLU 56 3961 5033 2553 -308 520 - 1110 ATÓM 456 C A GLU 56 -10,222 27.875 63. 925 1,000 3 0.18 Anisa 456 CA GLU 56 4160 4504 2805 -734 1221 - 6 3 7 ATÓM 457 C GLU 56 -11,650 28.401 63820 1,000 3 3.50 Anisa 457 C GLU 56 4 324 4124 4 2 80 -535 14 89 - 8 9 2 ATÓM 458 0 GLU 56 -12,470 28.149 64. 7 08 1. 000 4.44

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S / 03860

Anisa 458 ABOUT GLU 5 6 3864 8872 4150 93 io: L3 1011 ATÓM 459 CB GLU 56 -9,403 28.978 6 4 .615 1. 000 • 3-S. 8 5 Anisa 459 CB GLU 56 5037 5109 3475 -221 574 - 1 7 2 1 ATÓM 460 CG GLU 56 -8,192 28.508 65401 1,000 8.63 Anisa 460 CG GLU 56 4804 7152 2721 -337 763 -1692 ATÓM 4 61 CD GLU 56 -7,395 29.699 65916 1,000 5.55 Anisa 461 CD GLU 56 5,576 7183 4 5 4 6 -24 -295-2 3 3 0 ATÓM 462 OE1 GLU 56 -7,935 30.828 65.888 1,000 5.54 Anisa 462 OE1 GLU 56 7344 7247 6512 586 2570 - 3 0 5 8 ATÓM 463 OE2 GLU 56 -6,246 29.492 66350 1,000 5 0.41 Anisa 463 OE2 GLU 56 4050 10497 4606 -1066 1163 - 2 0 6 4 ATÓM 464 N HIS 57 -11,890 29.289 62866 1,000 2.20 Anisa 464 N HIS 57 3273 4700 4261 -549 1540 - 6 6 0 ATÓM 465 CA HIS 57 -13,101 30.078 62909 1,000 3 3.38 Anisa 4 65 CA HIS 57 3795 4885 4002 -110 1552 - 1 2 3 8 ATÓM 466 C HIS 57 -13,981 29.873 61697 1. 000 3 2.85 Anisa 466 C HIS 57 3380 4736 4367 278 1506 -1797 ATÓM 467 ABOUT HIS 57 -15,012 30.533 61571 1,000 3 7.09 Anisa 467 ABOUT HIS 57 3362 4733 5998 276 1087 - 2 2 0 4 ATÓM 468 CB HIS 57 -12,802 31.573 62976 1,000 7.39 Anisa 468 CB HIS 57 4327 4959 4922 -193 1402-1 9 7 0 ATÓM 469 CG HIS 57 -11,981 31.949 64162 1,000 3 6.99 Anisa 469 CG HIS 57 4111 5046 4896 680 1344 - 2 3 1 8 ATÓM 470 ND1 HIS 57 -12,465 31.917 65.453 1,000 8.84 Anisa 470 ND1 HIS 57 5090 4844 4823 -171 1361 - 1 5 9 8 ATÓM 471 CD2 HIS 57 -10,707 32.387 64232 1,000 7.91 Anisa 471 CD2 HIS 57 5259 4197 4947 -891 1543 -2 8 2 8 ATÓM 472 CE1 HIS 57 -11,510 32.305 66275 1,000 4 0.37 Anisa 472 CE1 HIS 57 5481 5191 4668 -243 1087 - 13 5 1 ATÓM 473 NE2 HIS 57 -10,441 32.592 65552 1,000 35.63 Anisa 473 NE2 HIS 57 4420 4376 4743 980 799 -1492 ATÓM 474 N GLY 58 -13,464 29068 60786 1,000 32.06 Anisa 474 N GLY 58 4402 3186 4594 1572 - 15 2 5 ATÓM 475 CA GLY 58 -14,290 28731 59.627 1,000 3 5.74 Anisa 475 CA GLY 58 4508 4402 4669 -1129 1877 - 1 8 9 4 ATÓM 476 C GLY 58 -15,449 27.859 60099 1,000 3 1.52 Anisa 476 C GLY 58 3317 3688 4969 308 1657 - 5 8 3 ATÓM 477 ABOUT GLY 58 -15,245 26.952 60922 1,000 32.66 Anisa 477 ABOUT GLY 58 4561 4176 3674 -204 624 - 1 0 11 ATÓM 478 N SER 59 -16,632 28.152 59.574 1,000 3 1.03 Anisa 478 N SER 59 3786 3623 4379 519 1142-14 14 2 ATÓM 479 CA SER 59 -17,823 27.359 59.859 1,000 32.03 Anisa 479 CA SER 59 3305 3925 4939 757 850 -1188 ATÓM 480 C SER 59 -17,763 26.034 59.117 1,000 7.27 Anisa 480 C SER 59 3654 4001 6507 0 2065 - 1 69 2 ATÓM 481 ABOUT SER 59 -16,987 25.858 58.181 1,000 3 1.23 Anisa 481 ABOUT SER 59 3027 3655 5184 613 1003 - 1 2 3 4 ATÓM 482 CB SER 59 -19,077 28.136 59444 1,000 3 9.80 Anisa 482 CB SER 59 3930 5925 5266 1707 -545 - 2 8 4 ATÓM 483 OG SER 59 -19,252 28.159 58029 1,000 5.38 Anisa 483 OG SER 59 3505 4800 5137 355 119 - 16 2 4 ATÓM 484 N GLU 60 -18,589 25.065 59.507 1,000 6.32 Anisa 484 N GLU 60 5438 6083 6078 -2395 2115 - 2 6 0 0 ATÓM 485 CA GLU 60 -18,573 23.801 58754 1,000 4.21 Anisa 485 CA GLU 60 3381 4798 4818 -960 715 - 12 3 8 ATÓM 486 C GLU 60 -19,033 24.055 57.330 1,000 4.22 Anisa 486 C GLU 60 4659 3711 4632 455 1377 - 8 4 7 ATÓM 487 ABOUT GLU 60 -18,616 23.437 56.361 1. 000 9.91 Anisa 487 ABOUT GLU 60 3708 3040 4615 -679 2037 - 6 0 3 ATÓM 488 CB GLU 60 -19,390 22nd 742 59.488 1. 000 8.26 Anisa 488 C B GLU 60 5012 5567 3958 -1599 748 - 1 0 0 1

SUBSTTTUTE SHEET (RULE 26) \ V () 99/33994

PCT / GB98 / 03S60

AND THAT!·'. 4S9 CG GLU b 0 -18,625 2 2. 1S 2 60073 1.000 4 2.01 ANI SOU 489 CG GLU 6 0 5470 5439 5055 503 -950-7 8 2 ATÓM 490 CD GLU 60 -17,307 21.528 60.312 1. 000 4 5.3 Anisa 490 CD GLU 60 4036 7496 5695 -886 1094 - 2 2 7 6 ATÓM 491 OE1 GLU 60 -17,219 20.867 59.264 1. 000 9 9.6 9 Anisa 491 OE1 GLU 60 5383 6689 6809 -864 1730–2838 ATÓM 492 OE2 GLU 60 -16,323 21.659 61084 1.000 4 3.6 2 Anisa 492 OE2 GLU 60 4677 4974 6924 -1984 109-1 ATÓM 493 N ALA 6 1 -19,928 25.028 57.167 1.000 3 4.2 6 Anisa 493 N ALA 61 3091 3912 6014 -81 1209 - 1 2 3 ATÓM 494 CA ALA 61 -20,408 25.324 55823 1,000 3 3.0 7 Anisa 494 CA ALA 61 1647 4409 6 5 0 7 -228 657 - 1 1 0 6 ATÓM 495 C ALA 61 -19,314 25.876 54.938 1,000 3 0.6 9 Anisa 495 C ALA 61 2053 3742 5866 -59,640 - 1 0 6 6 ATÓM 496 ABOUT ALA 61 -19. 138 25.482 53.790 1,000 3 1.1 5 Anisa 496 ABOUT ALA 61 2754 2893 61 89 31,793 - 1 2 8 5 ATÓM 497 CB ALA 61 -21,543 26.336 5. 9 3 2 1.000 3 4.4 3 Anisa 497 CB ALA 61 2783 4403 5E 97 288 1211 - 1 6 5 0 ATÓM 498 N GLU 62 -18,568 26.824 55 .498 1,000 2 8.8 0 Anisa 498 N GLU 62 2168 3404 5371 -9 915-9 6 4 ATÓM 499 CA GLU 62 -17,478 27.395 54.704 1,000 2 6.7 8 Anisa 499 C A GLU 62 2339 2374 5461 422 871 - 4 1 3 ATÓM 500 C GLU 62 -16,432 26.330 54389 1.000 22.61 Anisa 500 C GLU 62 2569 1621 4402 83 1049 - 3 7 7 ATÓM 501 ABOUT GLU 62 -15,851 26.316 53.289 1,000 2 4.4 1 Anisa 501 ABOUT GLU 62 2399 2669 4209 -132 801 5 5 8 ATÓM 502 CB GLU 62 -16,861 28.591 55.429 1,000 3 2.8 6 Anisa 502 CB GLU 62 3129 2117 7239 251 2038 - 1 3 5 8 ATÓM 503 CG GLU 62 -17,739 29.834 55554 1,000 3 4.6 9 Anisa 503 CG GLU 62 2824 2859 7499 915 -95 - 1 4 3 0 ATÓM 504 CD GLU 62 -17,274 30.810 56.616 1,000 3 8.9 3 Anisa 504 CD GLU 62 4998 2780 7014 1623 224 - 1 8 2 0 ATÓM 505 OE1 GLU 62 -16,861 30.391 57.717 1.000 40.92 Anisa 505 OE1 GLU 62 4844 3636 7058 1267 34 - 1 6 7 3 ATÓM 506 OE2 GLU 62 -17,324 32.041 56385 1.000 45.13 Anisa 506 OE2 GLU 62 7600 2889 6658 -525 1698 - 1 0 9 9 ATÓM 507 N LYS 63 -16,193 25.431 55.345 1.000 2 5.2 0 Anisa 507 N LYS 63 2470 2380 4723 312 1049 8 ATÓM 508 CA LYS 63 -15,214 24.369 55 .207 1.000 21.62 Anisa 508 CA LYS 63 2608 2894 2712 690 349 - 4 4 6 ATÓM 509 C LYS 63 -15,708 23.397 54 .147 1,000 2 2.4 2 Anisa 509 C LYS 63 2930 3038 2549 84 433 - 2 1 6 ATÓM 510 ABOUT LYS 63 -14,913 23.038 53 289 1,000 2 4.1 7 Anisa 510 ABOUT LYS 63 3340 2354 3491 239 782 - 7 9 0 ATÓM 511 CB LYS 63 -14,940 23.650 56.534 1,000 2 4.5 0 Anisa 511 CB LYS 63 3411 3057 2842 42 - 105 - 2 9 9 ATÓM 512 CG LYS 63 -13,963 24.465 57.381 1,000 2 7.5 8 Anisa 512 CG LYS 63 4640 2792 304 5 -302 -465 3 3 6 ATÓM 513 CD LYS 63 -13,866 23.937 58.811 1,000 2 6.0 9 Anisa 513 CD LYS 63 3132 3570 3211 305 -575-1 ATÓM 514 CE LYS 63 -12,761 24.695 59.560 1.000 28.96 Anisa 514 CE LYS 63 4342 3579 3OE3 -317 -286-7 9 2 ATÓM 515 NZ LYS 63 -12,927 24.614 61.030 1.000 35.00 Anisa 515 NZ LYS 63 4884 5356 3057 64 -298-8 1 7 ATÓM 516 N ARG 64 -17,007 23.112 54143 1.000 2 9.8 2 Anisa 516 N ARG 64 3238 2676 5418 -533 1111 1 2 5 ATÓM 517 CA ARG 64 -17,521 22.169 53.118 1. 000 2 5.5 7 Anisa 517 CA ARG 6 4 2396 2474 484 1 -170 1253 - 9 6 2 ATÓM 518 C ARG 64 -17,417 22.735 51.708 1. . 000 2 8.4 5 Anisa 518 C ARG 64 3022 2681 5106 153 1368 - 5 6 2 ATÓM 519 ABOUT ARG 64 -17,149 21.981 50.759 1.000 2 2.5 7

SUBSTTTUTE SHEET (RULE 25)

WO 99/33994

PCT / GB98 / 03860

Anisa 519 0 ARG ó 4 1672 2466 4 4 3 6 -71 148 - 3 8 5 ATÓM 520 CB ARG 6 4 -18 .937 21.809 53 .537 1. 000 · > 3:48 Anisa 520 CB ARG 64 2669 4144 5526 -809 1483 - 1 0 2 8 ATÓM 521 CG ARG 64 -19,094 20.442 54189 1,000 5.55 Anisa 521 CG ARG 64 4444 4749 8116 -2,443 1344 - 1 5 3 ATÓM 522 CD ARG 64 -20,557 19 Dec 985 54.080 1,000 5 9.48 Anisa 522 CD ARG 64 5723 6760 10116 -3,977 -2862 2 4 6 1 ATÓM 523 NE ARG 64 -20,759 19.485 52.714 1,000 77.63 Anisa 523 NE ARG 64 10254 9303 9938 -4,031 -4193 2666 ATÓM 524 CZ ARG 64 -21. 166 20.236 51.696 1,000 6 0.23 Anisa 524 CZ ARG 64 5289 6952 10644 -1128 -4335 5 0 1 ATÓM 525 NH1 ARG 64 -21,424 21.528 51892 1,000 9 1.64 Anisa 525 NH1 ARG 64 18286 5072 11461 -5,082 -3133 - 7 5 ATÓM 526 NH2 ARG 64 -21,286 19.711 50.489 1,000 4 3.67 Anisa 526 NH2 ARG 64 3318 4095 9178 -183 -1522 2 0 8 5 ATÓM 527 N ALA 65 -17,624 24.041 51.515 1,000 6.71 Anisa 527 N ALA 65 1907 2770 5472 189 935 - 5 5 6 ATÓM 528 CA ALA 65 -17,522 24.661 50.199 1,000 2 4.91 Anisa 528 CA ALA 65 1798 2379 5288 280 417-7 5 4 ATÓM 529 C ALA 65 -16,109 24.575 49.595 1,000 2 1.81 Anisa 529 C ALA 65 1808 2408 4071 597 155-6 6 6 ATÓM 530 0 ALA 65 -15,935 24.724 48.381 1,000 4.13 Anisa 530 0 ALA 65 2127 3076 3964 224 -220 - 4 8 ATÓM 531 CB ALA 65 -18,023 26.096 50.221 1,000 3 1.78 Anisa 531 CB ALA 65 3096 2984 5993 1337 1401 - 4 5 4 ATÓM 532 N VAL 66 -15,098 24.306 50.426 1,000 19:29 Anisa 532 N VAL 66 1836 1880 3614 466 360-5 5 1 ATÓM 533 CA VAL 66 -13,723 24.167 49953 1,000 18:17 Anisa 533 CA VAL 66 1636 1653 3616 204 80 - 4 8 7 ATÓM 534 C VAL 66 -13,166 22.767 50.248 1,000 15:18 Anisa 534 C VAL 66 1516 1638 2613 120 126 - 5 6 1 ATÓM 535 0 VAL 66 -11,959 22.623 50.353 1,000 17.63 Anisa 535 0 VAL 66 1567 ' 2071 3060 217 -106 - 3 1 6 ATÓM 536 CB VAL 66 -12,784 25.277 50.437 1,000 18.91 Anisa 536 CB VAL 66 2175 1576 3433 183 -135-5 5 9 8 ATÓM 537 CG1 VAL 66 -13,139 26.627 49.805 1,000 2 0.60 Anisa 537 CG1 VAL 66 2067 1751 4010 219 593-8 3 ATÓM 538 CG2 VAL 66 -12,736 25.373 51.945 1,000 2 1.61 Anisa 538 CG2 VAL 66 2689 2066 3455 102 22 - 6 0 4 ATÓM 539 N THR 67 -14,048 21792 50343 1,000 18:30 Anisa 539 N THR 67 1761 1614 3577 -20 -6 - 5 ATÓM 540 CA THR 67 -13,673 20.403 50.563 1,000 17:18 Anisa 540 CA THR 67 1927 1656 2946 -32 51 - 5 5 6 ATÓM 541 C THR 67 -13,979 19.566 49.332 1,000 16:52 Anisa 541 C THR 67 1763 1742 2773 21 27 - 4 7 6 ATÓM 542 0 THR 67 -15,107 19.613 48.811 1,000 18:13 Anisa 542 0 THR 67 1750 2211 2929 73 - 86 - 3 8 3 ATÓM 543 CB THR 67 -14,373 19.791 51782 1,000 18:54 Anisa 543 CB THR 67 2202 2014 2827 192 224-4 4 2 ATÓM 544 OG1 THR 67 -14,060 20.554 52.961 1,000 2 0.14 Anisa 544 OG1 THR 67 2481 2251 2920 -108 155 - 4 7 8 ATÓM 545 CG2 THR 67 -13,912 18.364 52.017 1,000 2 0.04 Anisa 545 CG2 THR 67 2393 2016 3203 29 - 86 - 2 3 5 ATÓM 546 N SER 68 -13,030 18818 48.821 1,000 16.71 Anisa 546 N SER 68 1612 1720 3018 -135 153 - 4 9 8 ATÓM 547 C A SER 68 -13 .281 17.947 47.688 1,000 16:33 Anisa 547 CA SER 68 1508 1631 3065 -184 365 - 5 7 1 ATÓM 548 C SER 68 -14,223 16.795 48.057 1. 000 14.85 Anisa 548 C SER 68 1194 1775 2672 -81 198 - 4 4 8 ATÓM 549 0 SER 68 -14,303 16.431 49.233 1,000 16:36 Anisa 549 0 SER 68 1783 1775 2659 -145 191 - 4 8 1

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT GB9SO3S60

ATÓM 550 CB SER 6 a Anisa 550 CB SER 6S ATÓM 551 OG SER 68 Anisa 551 OG SER 68 ATÓM 552 N PRO 69 Anisa 552 N PRO 69 ATÓM 553 C A PRO 69 Anisa 553 CA PRO 69 ATÓM 554 C PRO 69 Anisa 554 C PRO 69 ATÓM 555 ABOUT PRO 69 Anisa 555 ABOUT PRO 69 ATÓM 556 CB PRO 69 Anisa 556 CB PRO 69 ATÓM 557 CG PRO 69 Anisa 557 CG PRO 69 ATÓM 558 CD PRO 69 Anisa 558 CD PRO 69 ATÓM 559 N VAL 70 Anisa 559 N VAL 70 ATÓM 560 C A VAL 70 Anisa 560 CA VAL 70 ATÓM 561 C VAL 70 Anisa 561 C VAL 70 ATÓM 562 ABOUT VAL 70 Anisa 562 ABOUT VAL 70 ATÓM 563 CB VAL 70 Anisa 563 CB VAL 70 ATÓM 564 CG1 VAL 70 Anisa 564 CG1 VAL 70 ATÓM 565 CG2 VAL 70 Anisa 565 CG2 VAL 70 ATÓM 566 N PRO 71 Anisa 566 N PRO 71 ATÓM 567 CA PRO 71 Anisa 567 CA PRO 71 ATÓM 568 C PRO 71 Anisa 568 C PRO 71 ATÓM 569 ABOUT PRO 71 Anisa 569 0 PRO 71 ATÓM 570 CB PRO 71 MISOU 570 CB PRO 71 ATÓM 571 CG PRO 71 Anisa 571 CG PRO 71 ATÓM 572 CD PRO 71 Anisa 572 CD PRO 71 ATÓM 573 N THR 72 Anisa 573 N THR 72 ATÓM 574 CA THR 72 Anisa 574 CA THR 72 ATÓM 575 C THR 72 Anisa 575 C THR 72 ATÓM 576 ABOUT THR 72 Anisa 576 ABOUT THR 72 ATÓM 577 CB THR 72 Anisa 577 CB THR 72 ATÓM 578 OG1 THR 72 Anisa 578 OG1 THR 72 ATÓM 579 CG2 THR 72 Anisa 579 CG2 THR 72 ATÓM 580 U MET 73

- 1 1 .95S 17.303 47.257 1. 000 1 ~. S 4 1459 2139 3182 -37 64 ·, - -10,998 18.259 4Ó.904 1,000 17:21 1659 1987 2893 -75 364-4 9 -14,929 16.284 47054 1. 000 15.89 1574 1661 2803 -201 -103 - 2 7 0 -15,877 15.182 47.339 1,000 16:42 1428 1903 2 908 -251 -148-218 -15,168 13.889 47.684 1,000 17:22 1633 1578 3 331 -199 2 6 7 - 6 2 4 -15,794 12.997 48287 1,000 18:35 1815 1760 3399 -365 232-3 7 6 -16,712 15.057 46.060 1,000 16.75 1354 2279 2 73 3 -360 155-7 2 9 -15,799 15.637 45.008 1,000 16.72 1553 1971 2827 -359 39 - 4 5 2 -15,059 16.797 45. 681 1,000 17:10 1918 1804 2776 -344 -119- 3 1 3 -13,884 13.746 47.366 1,000 7.18 1716 1764 3384 -89 292-2 2 1 5 -13,100 12.594 47.824 1,000 17:34 1763 1851 2974 -20 260-1 9 6 -11,995 13.142 48.720 1,000 17:59 2207 1686 27B8 -180 159-14 2 -11,431 14.186 48.389 1,000 18:59 1794 1688 3581 -4 9 15 2 -12,429 11.757 46.724 1,000 18:10 1922 1756 3199 -353 560 - 4 5 6 -13,441 10.754 46.213 1,000 2 0.54 1927 2611 3268 -369 76 - 6 7 3 -11,760 12.608 45.642 1,000 17.65 2379 1806 2520 145 9 10 -11,697 12.466 49.815 1,000 16:21 1653 1810 265'5 -34 465 - 1 5 6 -10,839 13.091 50.833 1,000 17:32 1795 1931 2854 -121 184-1 -9,356 12.804 50.590 1,000 17.67 1865 1927 2921 46 -57,156 -8,585 12.223 51.350 1,000 2 0.57 2218 2247 3350 424 27 4 7 4 -11,362 12.458 52.117 1,000 19.76 2976 1862 2668 -347 478 - 3 0 4 -11,721 11.056 51.670 1,000 8.19 2838 1805 2608 -267 259-2 3 4 -12,323 11.220 50286 1,000 17.97 2314 1974 2538 -390 451-16 7 -8,894 13.338 49.446 1,000 17:15 1677 2231 2610 -215 -17 - 1 5 6 -7,573 13.012 48. 935 1,000 16.83 1721 1863 2813 -60 -134-4 4 2 -6,490 14,000 49.358 1,000 15:20 1791 1623 2 3 62 -304 163-7 3 -5,320 13.729 49.104 1,000 17:49 1776 1961 2908 -61 -31- 2 2 5 -7,533 12.971 47.399 1,000 16:18 1552 1848 2748 -146 -86-2 2 6 1 -8,091 14.238 47.005 1. 000 17.81 1856 1880 3 0 31 -34 115 -19 1 -8,338 11.816 46.825 1,000 17:49 1953 2087 2 6 05 -550 181 - 3 2 8 -6,877 15.098 4 9. S '8 7 1. 000 17 7 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98O3860

Anisa 5S0 N MET 73 2057 1748 2951 -58 -25-3-426 ATÓM 5S1 C A MET 73 -5,667 16.117 50394 1.000 1 6 \ 5 8 Anisa 581 C A MET 73 1796 1708 2797 88 -302-3 3 4 0 ATÓM 582 C MET 73 -5,073 16618 49.198 1.000 16.65 Anisa 582 C MET 73 1514 1787 3027 241 -162-420 ATÓM 583 ABOUT MET 73 -3,911 17.039 49.292 1.000 1 9.3 9 Anisa 583 ABOUT MET 73 1705 2313 3348 -112 -240 5 5 0 ATÓM 584 CB MET 73 -4,925 15 Dec 531 51469 1,000 2 0.5 6 Anisa 584 CB MET 73 2099 2629 3083 345 -507-2 8 6 ATÓM 585 CG MET 73 -5,703 15.154 52715 1,000 3 0.3 3 Anisa 585 CG MET 73 3008 5133 3384 -69 -609 1 0 2 7 ATÓM 586 SD MET 73 -4,692 14.263 53.891 1,000 3 6.1 3 Anisa 586 SD MET 73 4121 5050 4558 336 -917 1 5 9 6 ATÓM 587 CE MET 73 -3,165 13.987 53.082 1,000 5 8.0 7 Anisa 587 CE MET 73 2810 8820 10435 975 -1592- 3 1 3 8 ATÓM 588 N ARG 74 -5,687 16.632 48.025 1,000 1 6.8 3 Anisa 588 N ARG 74 1699 1714 2982 -6 -211 ATÓM 589 CA ARG 74 -5,099 17.215 46.817 1,000 1 5.8 7 Anisa 589 CA ARG 74 1365 1618 3046 -17 51 - 3 2 5 ATÓM 590 C ARG 74 -5,359 18.714 46.761 1.000 1 4.2 2 Anisa 590 C ARG 74 1484 1651 2269 141 -32-4 4 2 ATÓM 591 0 ARG 74 -4,472 19.488 46.353 1,000 1 5.4 5 Anisa 591 0 ARG 74 1525 1758 2586 -12 -46-7 3 ATÓM 592 CB ARG 74 -5,675 16.530 45566 1.000 15.68 Anisa 592 CB ARG 74 1330 1667 2959 160 -14 -311 ATÓM 593 CG ARG 74 -4,890 16.941 44.299 1.000 1 6.4 6 Anisa 593 CG ARG 74 1325 1870 3059 -176 55 - 3 9 5 ATÓM 594 CD ARG 74 -5,655 16.396 43.072 1.000 1 6.3 7 Anisa 594 CD ARG 74 1789 1533 2899 -181 -8 - 1 7 7 ATÓM 595 NE ARG 74 -4,840 16.601 41.857 1.000 1 9.2 1 Anisa 595 NE ARG 74 2289 1990 3020 -142 241 - 1 5 7 ATÓM 596 CZ ARG 74 -4,944 17.626 41.039 1.000 17.0 0 Anisa 596 CZ ARG 74 1545 2351 2562 -67 27 - 1 4 7 ATÓM 597 NH1 ARG 74 -5,878 18.573 41.213 1.000 1 8.00 Anisa 597 NH1 ARG 74 1818 2383 2638 51 - 66 - 2 2 0 ATÓM 598 NH2 ARG 74 -4,144 17.703 39.987 1,000 2 0.5 0 Anisa 598 NH2 ARG 74 2285 2972 2532 -110 310 - 3 7 7 ATÓM 599 N ARG 75 -6,579 19.151 47.101 1.000 1 5.2 8 Anisa 599 N ARG 75 1755 1544 2507 138 340 - 1 7 3 ATÓM 600 CA ARG 75 -6,999 20.550 46.980 1,000 1 4.6 8 Anisa 600 CA ARG 75 1679 1627 2272 237 98 - 1 5 0 ATÓM 601 C ARG 75 -7,956 20.869 48.122 1.000 14.75 Anisa 601 C ARG 75 1445 1747 2414 125 133 - 2 3 3 ATÓM 602 0 ARG 75 -8,760 19.989 48.460 1,000 1 8.1 2 Anisa 602 0 ARG 75 1677 2109 3101 -156,458 - 4 3 3 ATÓM 603 CB ARG 75 -7,747 20.804 45.668 1.000 15.59 Anisa 603 CB ARG 75 1577 2030 2317 1 46-106 ATÓM 604 CG ARG 75 -6,848 20.634 44.441 1.000 1 5.6 3 Anisa 604 CG ARG 75 1495 2110 2334 9,147 2 2 0 ATÓM 605 CD ARG 75 -5,712 21.618 44.334 1.000 1 5.5 9 Anisa 605 CD ARG 75 1658 1792 2475 11 140 - 1 0 ATÓM 606 NE ARG 75 -5,061 21.601 43.011 1.000 1 5.2 5 Anisa 606 NE ARG 75 1421 1779 2596 123 227 144 ATÓM 607 CZ ARG 75 -3,957 20.865 42.732 1,000 1 4.9 0 Anisa 607 CZ ARG 75 1079 2361 2221 71 -86,242 ATÓM 608 NH1 ARG 75 -3,405 20.091 43.664 1.000 1 6.1 8 Anisa 608 NH1 ARG 75 1804 1722 2623 -134 -387 3 3 6 ATÓM 609 NH2 ARG 75 -3,418 20.940 41.518 1,000 1 5.8 3 Anisa 609 NH2 ARG 75 1677 2107 2232 -192 221 0 ATÓM 610 N GLY 76 -7,895 22.086 48.651 1,000 1 6.0 6 Anisa 610 U GLY 76 1686 1904 2513 110 220 - 4 6 4

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ATÓM ó 11 C A GLY 7 ô -8 .858 22 53 2 49.637 1. 000 1 ó. ó 7 Anisa 611 C A GLY 7b 1650 2260 2 4 2 5 -70 198. -6 12 ATÓM 512 C GLY 7 6 -8,602 22.002 5 J .036 1. 000 16:32 Anisa 612 C GLY 76 1584 2014 2 60 2 -126 26S-3 4 7 ATÓM 613 ABOUT GLY 76 -7,469 21.651 51.370 1. 000 1 6. S 7 Anisa 613 ABOUT GLY 76 1638 1998 2773 -45 30S-2 18 ATÓM 614 N PHE 77 -9,643 22.025 51863 1,000 1 6. S 8 Anisa 614 N PHE 77 1597 2141 2675 -7,283 - 1,929 1 ATÓM 615 CA PHE 77 -9,584 21.646 53.274 1,000 17.61 Anisa 615 C A PHE 77 1838 2196 2656 109 328 - 1 2 4 ATÓM 616 C PHE 77 -9,776 20.154 53.512 1. 000 17.64 Anisa 616 C PHE 77 1855 2248 2600 -68 243-1 8 5 ATÓM 617 ABOUT PHE 77 -10,589 19.528 52.831 1,000 18:23 Anisa 617 ABOUT PHE 77 1844 2488 2594 -183 357 - 2 3 0 ATÓM 618 C D PHE 77 -10,698 22nd 383 53998 1,000 17.70 Anisa 618 CB PHE 77 1730 2515 24 30 162 6 5 - 3 4 5 ATÓM 619 CG PHE 77 -10,877 22.081 55.473 1,000 19.61 Anisa 619 CG PHE 77 2405 2530 2515 195 261-516 ATÓM 620 CD1 PHE 77 -9,966 22.594 56 .395 1,000 2.27 Anisa 620 CD1 PHE 77 2514 3523 2426 431 - 23 - 5 2 7 ATÓM 621 CD2 PHE 77 -11,917 21.285 55.941 1,000 2 1.31 Anisa 621 CD2 PHE 77 3282 2070 2743 36 615 2 8 8 ATÓM 622 CE1 PHE 77 -10,116 22294 57742 1,000 2 1.05 Anisa 622 CE1 PHE 77 2719 2768 2510 171 221 - 3 4 9 ATÓM 623 CE2 PHE 77 -12,079 20.991 57.300 1,000 2 5.09 Anisa 623 CE2 PHE 77 2967 4120 244 7 -501 625-8 2 6 ATÓM 624 CZ PHE 77 -11,175 21.523 58207 1,000 2 3.79 Anisa 624 CZ PHE 77 2263 3681 3095 -1 376-7 5 6 ATÓM 625 N THR 78 -9,022 19.631 54.490 1,000 17.64 Anisa 625 N THR 78 1616 2161 2925 37,336 1 ATÓM 626 C A THR 78 -9,296 18279 54.983 1,000 18:12 Anisa 626 CA THR 78 1926 2243 2717 -157 624-2 8 ATÓM 627 C THR 78 -9,291 18.316 56.505 1,000 18.66 Anisa 627 C THR 78 2120 2308 2663 -367 519-2 8 8 ATÓM 628 0 THR 78 -8,335 18.821 57095 1,000 2 1.42 Anisa 628 0 THR 78 2158 2883 3098 -432 90177 ATÓM 629 CB THR 78 -8,252 17.242 54521 1,000 2 1.00 Anisa 629 CB THR 78 2973 2067 2939 113 427 - 5 7 4 ATÓM 630 OG1 THR 78 -8,027 17.392 53.104 1,000 2 1.18 Anisa 630 OG1 THR 78 2544 2671 283 3 160 317-7 7 3 ATÓM 631 CG2 THR 78 -8,735 15.832 54.300 1,000 6.65 Anisa 631 CG2 THR 78 3759 2227 414 L -275 854 - 6 1 8 ATÓM 632 N GLY 79 -10,311 17.804 57181 1,000 2 0.36 Anisa 632 N GLY 79 2669 2379 2690 -670 630 - 1 3 4 ATÓM 633 CA GLY 79 -10,344 17.679 58. (523 1,000 2 5.96 Anisa 633 CA GLY 79 3871 3249 2745 -790 576 375 ATÓM 634 C GLY 79 -10,029 16.238 59.039 1,000 9.70 Anisa 634 C GLY 79 6407 3542 5135 -1658 -1943 1 5 1 1 ATÓM 635 0 GLY 79 -10,623 15.303 58.491 1,000 3 1.02 Anisa 635 0 GLY 79 4327 3187 4272 -404 419-7 5 ATÓM 636 N LEU 80 -9,069 16.055 59.936 1,000 6.07 Anisa 636 N LEU 80 4380 4536 4788 1381 -564-8 3 5 ATÓM 637 C A LEU 80 -8,634 14.713 60340 1,000 3 2.52 Anisa 637 C A LEU 80 3640 4083 4 63 2 611 -502-8 9 8 ATÓM 638 C LEU 80 -9,131 14311 61716 1,000 3 9.82 Anisa 638 C LEU 80 5051 4652 542E -128 419 - 5 3 8 ATÓM 639 0 LEU 80 -9,998 14.963 62305 1,000 3 7.05 Anisa 639 0 LEU 80 5057 3807 5213 -292 667 8 7 ATÓM 640 CB LEU 80 -7 .122 14.580 60265 1,000 8.36 Anisa 640 CB LEU 80 3821 5456 5299 1568 -33 - 1 4 0 7 ATÓM 64 1 CG LEU 80 -6,488 14.753 58.883 1,000 8.27

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

Anisa O41 CG LEU 80 3714 5900 4926 72 = - 2 8 S-2588 ATÓM 642 CD1 LEU 80 -5,007 14 .359 58948 1. 000 4 · 5 ·. 4 1 Anisa 642 CDi LEU 80 2579 8505 6170 -1092 -76 3 7 ATÓM 643 CD2 LEU 80 -7,170 13. 856 57854 1. 000 4 0.75 Anisa 643 CD2 LEU 80 4296 5601 5587 872 -1965 -1793 ATÓM 644 N SER 98 -6,459 17.442 63. 930 1,000 6.72 Anisa 644 N SER 98 3404 6429 4118 -2,114 -699 1 9 4 8 ATÓM 645 C A SER 98 -5,629 17.877 62824 1,000 9.59 Anisa 645 C A SER 98 6031 5376 3635 -449 382 2 1 7 7 ATÓM 646 C SER 98 -6,402 18.372 61610 1,000 2 9.89 Anisa 646 C SER 98 3806 3509 4040 141 640 1 2 0 5 ATÓM 647 0 SER 98 -7,474 17.856 61304 1,000 8.27 Anisa 647 0 SER 98 4936 4300 5303 -1107 395 885 ATÓM 648 CB SER 98 -4,694 16.739 62358 1,000 4 4.06 Anisa 648 CB SER 98 3175 7425 6141 633 -752 2 7 0 4 ATÓM 649 OG SER 98 -3,672 17.368 61583 1,000 6.84 Anisa 649 OG SER 98 3497 6502 7797 95 -407 2 4 1 8 ATÓM 650 N MET 99 -5,829 19.317 60869 1,000 8.56 Anisa 650 N MET 99 5029 3458 2365 -1080 -550 546 ATÓM 651 CA MET 99 -6,426 19.941 59.700 1,000 2 1.44 Anisa 651 CA MET 99 2284 3549 2315 -182 157 132 ATÓM 652 C MET 99 -5,376 20229 58.624 1,000 19:16 Anisa 652 C MET 99 2306 2592 2382 -433 60137 ATÓM 653 0 MET 99 -4,232 20.575 58930 1,000 2 3.34 Anisa 653 0 MET 99 2489 3920 2460 -773 225 - 4 0 0 ATÓM 654 CB MET 99 -7,164 21.209 60105 1,000 25.20 Anisa 654 CB MET 99 3172 3375 3028 -572 662 - 5 4 7 ATÓM 655 CG MET 99 -8,481 20.965 60872 1,000 2 5.85 Anisa 655 CG MET 99 3172 3862 2787 -275 739-7 8 2 ATÓM 656 SD MET 99 -9,251 22.517 61389 1,000 2.21 Anisa 656 SD MET 99 4405 3750 4083 -133 1580 - 5 7 8 ATÓM 657 CE MET 99 -8,884 22.461 63.145 1,000 7 6.12 Anisa 657 CE MET 99 14782 11538 2603 -3321 3477 - 3 2 4 1 ATÓM 658 N CYS 100 -5,778 20.094 57.361 1,000 18.85 Anisa 658 N CYS 100 2434 2443 2285 -160 93194 ATÓM 659 CA CYS 100 -4,868 20.333 56.234 1,000 18:55 Anisa 659 CA CYS 100 2251 2380 2418 92 126 236 ATÓM 660 C CYS 100 -5,496 21.312 55228 1,000 16:26 Anisa 660 C CYS 100 1826 2031 2321 110 329 2 ATÓM 661 0 CYS 100 -6,728 21.308 55.071 1,000 17.69 Anisa 661 0 CYS 100 1741 2395 2586 -69 154 - 1 0 3 ATÓM 662 CB CYS 100 -4,604 18.982 55545 1,000 18:46 Anisa 662 CB CYS 100 2822 2081 2111 98 118 511 ATÓM 663 SG CYS 100 -3,243 18.974 54.329 1,000 2 2.76 Anisa 663 SG CYS 100 2622 2968 3058 307 391 1 0 ATÓM 664 N TYR 101 -4,697 22.069 54.498 1,000 17:49 Anisa 664 N TYR 101 1839 2473 2332 46 291 224 ATÓM 665 C A TYR 101 -5,117 22.874 53.373 1,000 15:38 Anisa 665 CA TYR 101 1946 1939 1960 -50 90-2 2 6 2 ATÓM 666 C TYR 101 -4,102 22.594 52.245 1,000 13.65 Anisa 666 C TYR 101 1676 1543 1967 -2-123-15 15 ATÓM 667 0 TYR 101 -2,896 22.629 52.475 1,000 15.95 Anisa 667 0 TYR 101 1611 2231 2217 -43 -232-2 2 1 2 ATÓM 668 CB TYR 101 -5 .122 24.382 53739 1,000 2.19 Anisa 668 CB TYR 101 2816 2082 2328 234 48-51 9 ATÓM 669 CG TYR 101 -5,617 25.109 52.498 1,000 17.85 Anisa 669 CG TYR 101 2084 1895 2804 18 -26-2 2 3 1 ATÓM 670 CDI TYR 101 -6,964 25.134 52.171 1,000 18:25 Anisa 670 CDI TYR 101 2042 1596 3298 29 28 4 9 6 ATÓM 671 CD2 TYR 101 -4 .730 25.778 51658 1,000 17.77 Anisa 671 CD2 TYPE. 101 2037 1611 3106 -46 - 125 - 1 2 7

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994 PCT'GB9S.'3838O

ATÓM 672 CE1 TYR 101 -7.406 - 35 - 25.796 5l · 036 1. 000 19.63 Anisa 6 7 2 CE1 TYR 101 1977 1776 3704 9 S - 2 4 K - 2: ’1 ATÓM 673 THROUGH TYF < 101 -5,147 2 ó. 3 8 ó 50.478 1,000 z 0. 4 p Anisa 673 THROUGH TYR 101 2060 2608 3108 239 40 18 2 ATÓM 67 4 CZ TYR 101 -6,504 26.392 53.166 1,000 2 C. 2 9 Anisa 674 CZ TYR 101 2187 2397 3 L27 -73 - 3 5 3 - 2 6 0 ATÓM 675 OH TYR 101 -6,932 26.995 49.000 1,000 2 3.34 Anisa 675 OH TYR 101 2790 2555 3 52 3 -3 -641 5 1 ATÓM Ó7 6 N SER 102 -4,648 22.210 51.097 1,000 14.60 Anisa 676 N SER 102 1618 1890 2 04 1 -61 -109 - 4 7 7 ATÓM 677 C A SER 102 -3,797 21792 49.980 1,000 14:52 Anisa 677 CA SER 102 1684 1802 2 0 3 0 -108 62-2 7 6 ATÓM 678 C SER 102 -4,011 22.670 48.747 1,000 14.99 Anisa 678 C SER 102 1545 1790 2361 -296 -41 2 1 ATÓM 679 ABOUT SER 102 -5,167 23.105 48.477 1,000 16.73 Anisa 679 ABOUT SER 102 1589 2342 2425 2 128-3 ATÓM 680 CB SER 102 -4,163 20.340 49.593 1,000 13.82 Anisa 680 CB SER 102 1692 1548 2013 174 9 - 1 2 8 ATÓM 681 OG SER 102 -3,996 19476 50.720 1,000 6.16 Anisa 681 OG SER 102 1886 2066 2153 97 -126 6 3 ATÓM 682 N MET 103 -2,978 22.775 47.920 1,000 14:47 Anisa 682 N MET 103 1568 1724 2206 51 -59,152 ATÓM 683 C A MET 103 -3,102 23.552 46.687 1,000 16:58 Anisa 683 C A MET 103 2194 1933 217 3 331 -74 2 5 3 ATÓM 684 C MET 103 -2,150 23.013 45.608 1,000 14:41 Anisa 684 C MET 103 1598 1793 2 083 -202 -210 6 3 ATÓM 685 ABOUT MET 103 -1,157 22.347 45. 920 1,000 16:24 Anisa 685 ABOUT MET 103 1527 2384 2259 -61 -23 4 6 8 ATÓM 686 CB MET 103 -2,716 25.004 46.835 1,000 8.78 Anisa 686 CB MET 103 6537 1318 3081 859 -207 3 6 6 ATÓM 687 CG MET 103 -3,258 25.986 47.801 1,000 2 2.60 Anisa 687 CG MET 103 2531 2157 3900 -161 -57 -: 2 9 1 ATÓM 688 SD MET 103 -2,338 27.505 47.506 1,000 2 0.60 Anisa 688 SD MET 103 2499 1927 34C0 -4 -164-2 2 6 ATÓM 689 CE MET 103 -2,587 27.945 45.804 1,000 2 1.63 Anisa 689 CE MET 103 2319 2601 3300 308 209 - 2 3 6 ATÓM 690 N GLY 104 -2,439 23.430 44378 1,000 15:44 Anisa 690 N GLY 104 1468 2228 2169 -68 -120 1 6 4 ATÓM 691 CA GLY 104 -1,511 23.199 43.276 1,000 16:13 Anisa 691 C A GLY 104 1688 2202 2241 42 65 4 6 9 ATÓM 692 C GLY 104 -1,583 24.355 42294 1,000 15.76 Anisa 692 C GLY 104 1706 1997 2286 -32 -194 3 8 8 ATÓM 693 ABOUT GLY 104 -1,987 25.478 42653 1,000 6.19 Anisa 693 ABOUT GLY 104 1953 2032 3256 -71 144 3 3 3 ATÓM 694 N THR 105 -1,151 24.092 41054 1,000 16.73 Anisa 694 N THR 105 1685 2385 2287 -375 -55 5 1 5 ATÓM 695 CA THR 105 -1,115 25.205 40.094 1,000 6.17 Anisa 695 CA THR 105 1725 2390 2369 -231 -148 5 7 7 ATÓM 696 C THR 105 -2,513 25.631 39.535 1,000 19:55 Anisa 696 C THR 105 1768 1817 384 2 -160 -346 5 2 5 ATÓM 697 ABOUT THR 105 -2,680 26.703 39059 1,000 2 2.41 Anisa 697 ABOUT THR 105 2262 2116 413 6 -119 -520 8 4 2 ATÓM 698 CB THR 105 -0,301 24.857 38.840 1,000 17:57 Anisa 698 CB THR 105 1759 2877 2038 -394 -343 3 7 7 ATÓM 699 OG1 THR 105 -0,865 23.675 38.217 1,000 18.66 Anisa 699 OG1 THR 105 2035 2449 2607 -140 -458 4 1 6 ATÓM 700 CG2 THR 105 1. 155 24.590 39.178 1. 000 18.95 Anisa 700 CG2 THR 105 1748 2853 2601 -105 -248 2 9 6 ATÓM 701 N ALA 106 -3,507 24.751 39.741 1,000 16:52 Anisa 701 N ALA 106 1596 2293 2 389 -180 -12 9 8 ATÓM 702 C A ALA 106 -4 .846 25.035 39218 1,000 16:59

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

Anisa 702 C A ALA 106 1692 1952 2660 -214 -209 243 ATÓM 703 C ALA 106 -5,848 24. 142 39.923 1,000 <-? ». 5 2 Anisa 703 C ALA 106 1651 1821 3186 26 -6l 5 5 5 5 ATÓM 704 0 ALA 106 -5,479 23.323 40.805 1. 000 17.88 Anisa 704 0 ALA 106 2038 2087 2668 59 -51,388 ATÓM 705 CB ALA 106 -4,862 24.838 37.713 1,000 2 0.31 Anisa 705 CB ALA 106 2331 2764 2620 -197 -403 440 ATÓM 706 N ASP 107 -7,149 24.329 39717 1,000 18:00 Anisa 706 N ASP 107 1576 2208 3057 -77 -120 4 9 ATÓM 707 C A ASP 107 -8,217 23.535 40.344 1,000 17:46 Anisa 707 CA ASP 107 1563 2191 2881 -83 -472 363 ATÓM 708 C ASP 107 -8,173 23753 41.859 1,000 17.74 Anisa 708 C ASP 107 1825 2044 2869 447 -269 362 ATÓM 709 0 ASP 107 -8,458 22.854 42.650 1,000 18.95 Anisa 709 0 ASP 107 1994 2230 2974 167 -133 402 ATÓM 710 CB ASP 107 -8,089 22.044 39.990 1,000 19.62 Anisa 710 CB ASP 107 2213 2300 2942 -394 -727 173 ATÓM 711 CG ASP 107 -8,370 21.842 38508 1,000 2 0.81 Anisa 711 CG ASP 107 1952 3093 2862 -138 -532 - 14 ATÓM 712 OD1 ASP 107 -9,369 22.369 37.976 1,000 2 5.84 Anisa 712 ODL ASP 107 2524 3967 3327 222 -1149 - 2 3 0 ATÓM 713 OD2 ASP 107 -7,544 21.168 37.844 1,000 2 5.86 Anisa 713 0D2 ASP 107 3314 2989 3523 391 -91- 8 9 ATÓM 714 N ASN 108 -7,893 24.962 42.298 1,000 18:18 Anisa 714 N ASN 108 2049 2075 2786 509 189 15 3 ATÓM 715 CA ASN 108 -7,831 25.263 43.740 1,000 17:10 Anisa 715 CA ASN 108 1804 1977 2715 266 291 327 ATÓM 716 C ASN 108 -9,158 25716 44314 1,000 17:11 Anisa 716 C ASN 108 1705 2061 2734 367 44149 ATÓM 717 0 ASN 108 -10,103 26.086 43.604 1,000 20.72 Anisa 717 0 ASN 108 2066 2377 3430 759 -248 245 ATÓM 718 CB ASN 108 -6,799 26379 43.969 1,000 19.90 Anisa 718 CB ASN 108 1770 2308 3483 186 298-1 7 1 ATÓM 719 CG ASN 108 -5,400 25.862 43.717 1,000 17:24 Anisa 719 CG ASN 108 1709 2212 2628 200 69 1 8 4 ATÓM 720 ODL ASN 108 -4,986 24.850 44.277 1,000 17:42 Anisa 720 ODL ASN 108 2003 1984 2631 109 11-62 ATÓM 721 ND2 ASN 108 -4,644 26.487 42.834 1,000 18:41 Anisa 721 ND2 ASN 108 2083 2326 2587 -82 300-1 8 ATÓM 722 N LEU 109 -9,308 25.509 45.607 1,000 18:09 Anisa 722 N LEU 109 1795 2294 2786 349 344 1 0 ATÓM 723 CA LEU 109 -10,532 25.803 46369 1,000 19:11 Anisa 723 CA LEU 109 1763 2200 3296 14,476 - 5 9 8 ATÓM 724 C LEU 109 -10,169 26.790 47.457 1,000 17:40 Anisa 724 C LEU 109 1682 1937 2990 251 129 - 2 0 6 ATÓM 725 0 LEU 109 -9,443 26.423 48.395 1,000 21:18 Anisa 725 0 LEU 109 2443 1922 3684 174 -520 2 ATÓM 726 CB LEU 109 -11,100 24.504 46.940 1,000 17:10 Anisa 726 CB LEU 109 1888 2142 2469 199 426-6 6 0 ATÓM 727 CG LEU 109 -11,520 23.425 45.944 1,000 7.18 Anisa 727 CG LEU 109 2515 1943 2409 190 -198- 3 6 3 ATÓM 728 CD1 LEU 109 -11,895 22.124 46.654 1,000 2 0.06 Anisa 728 CD1 LEU 109 2842 2406 2375 -331 - 175 - 2 0 0 ATÓM 729 CD2 LEU 109 -12,630 23.908 45.035 1,000 5.24 Anisa 729 CD2 LEU 109 3481 2892 3217 306 -992-1 1 1 1 ATÓM 730 N PHE 110 -10,609 28.036 47.313 1,000 17:25 Anisa 730 N PHE 110 1584 1926 3045 272 184 - 1 2 ATÓM 731 CA PHE 110 -10,235 29.071 48.277 1,000 18:20 Anisa 731 CA PHE 110 1751 1816 3346 169 221-16 0 ATÓM 732 C PHE 110 -11,409 29.567 49.106 1,000 19.93 Anisa 732 C PHE 110 2077 1609 3886 71,650 - 3 3 5

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ATÓM 733 0 P H E 1 10 -12,433 29. 94 S • 18.494 1,000 2 4.64 Anisa 733 ABOUT PHE 110 2051 2461 4 8 51 612 • J-2S-7 7 9 ATÓM 734 CB PHE 110 -9,607 30.243 4 7 .520 1. 000 19.92 Anisa 734 CB PHE 110 2367 1876 2 324 224 619-9 3 ATÓM 735 CG PHE 110 -8,380 29.986 4 6.688 1. 000 19:47 Ainis 735 CG PHE 110 2009 2209 3179 -321 327-7 9 1 ATÓM 736 CD1 PHE 110 -7,177 29.680 47 .287 1,000 2 0.59 Anisa 736 CD1 PHE 110 2071 2080 3674 -274 236 - 3 2 1 ATÓM 737 CD2 PHE 110 -8,437 30.035 45299 1,000 2 0.19 Anisa 737 CD2 PHE 110 2557 1914 3200 112 543-2 8 9 ATÓM 738 CE1 PHE 110 -6,034 29.454 46.559 1,000 2 1.06 Anisa 738 CE1 PHE 110 2020 2309 3673 -386 165-6 6 2 2 ATÓM 739 CE2 PHE 110 -7,277 29.811 44.547 1,000 2 0.77 Anisa 739 CE2 PHE 110 2495 2138 3 257 197 503 - 3 9 8 ATÓM 740 CZ PHE 110 -6,081 29.518 4'5. 175 1,000 2.42 Anisa 740 CZ PHE 110 2747 2092 3678 531 339 - 3 6 7 ATÓM 741 N PRO 111 -11,238 29.718 50.416 1,000 2 2.11 Anisa 741 N PRO 111 2250 2153 3996 -72 871 - 6 0 0 ATÓM 742 C A PRO 111 -12,287 30.389 51195 1,000 8.23 Anisa 742 CA PRO 111 3895 2210 4 621 698 1514 - 6 6 1 ATÓM 743 C PRO 111 -12,333 31.866 50.784 1,000 3 0.57 Anisa 743 C PRO 111 4528 2026 5 061 410 410-10 10 1 ATÓM 744 ABOUT PRO 111 -11,390 32.340 5C.115 1,000 3 1.71 Anisa 744 ABOUT PRO 111 4040 2236 5774 -179 -597-1 ATÓM 745 CB PRO 111 -11,799 30.250 52627 1,000 3.20 Anisa 745 CB PRO 111 5609 2702 4303 671 1671 - 7 0 0 ATÓM 746 CG PRO 111 -10,646 29.326 52647 1,000 2 6.04 Anisa 746 CG PRO 111 2742 3316 3835 -931 1324-1 9 2 ATÓM 747 CD PRO 111 -10,161 29.149 51.230 1,000 22:15 Anisa 747 CD PRO 111 2587 2307 3522 -471 541-6 6 3 3 ATÓM 748 N SER 112 -13,337 32.641 51.150 1,000 2.13 Anisa 748 N SER 112 7176 2716 6115 2074 1730 - 5 2 6 ATÓM 749 CA SER 112 -13,368 34.026 50672 1,000 4 4.05 Anisa 749 CA SER 112 6799 2255 7694 1107 -485-8 2 6 ATÓM 750 C SER 112 -13,262 34.157 49149 1,000 8.28 Anisa 750 C SER 112 13632 4498 7812 -1855 -2078 1 3 0 1 ATÓM 751 ABOUT SER 112 -12,347 34.825 48.646 1,000 9 5.18 Anisa 751 ABOUT SER 112 15991 11425 8747 -4,337 -70 1 9 8 5 ATÓM 752 CB SER 112 -12,493 35.069 51 .349 1,000 9.31 Anisa 752 CB SER 112 2247 4535 8153 580 1663 - 1 4 3 6 ATÓM 753 OG SER 112 -11,474 34.624 52.213 1,000 7.49 Anisa 753 OG SER 112 7213 2453 4579 806 748 - 1 1 5 2 ATÓM 754 N ASP 114 -9,515 37.322 49.945 1,000 3 6.40 Anisa 754 N ASP 114 3476 2118 8237 1254 4 03 1 4 8 5 ATÓM 755 CA ASP 114 -8,205 37.586 50.600 1,000 3 0.79 Anisa 755 CA ASP 114 3503 2856 534 0 1229 1240 996 ATÓM 756 C ASP 114 -7,242 36.402 50.648 1,000 6.16 Anisa 756 C ASP 114 2581 2,404 4955 601 1114 804 ATÓM 757 ABOUT ASP 114 -6,031 36.458 50338 1,000 5.45 Anisa 757 ABOUT ASP 114 2302 2503 4866 -43 602 131 ATÓM 758 CB ASP 114 -8,595 37.874 52075 1,000 4 3.68 Anisa 758 CB ASP 114 7509 2783 6304 1157 2727 - 2 0 0 ATÓM 759 CG ASP 114 -7,391 38.386 52835 1,000 4 6.96 Anisa 759 CG ASP 114 9259 3225 5359 2517 519 107 ATÓM 760 OD1 ASP 114 -6,487 38.959 52.189 1,000 8 3.49 Anisa 760 OD1 ASP 114 13724 9866 8132 -6,354 650 - 3 0 5 7 ATÓM 761 OD2 ASP 114 -7,370 38.262 54.071 1.000113.59 Anisa 761 OD2 ASP 114 27880 10550 4730 -6,984 - 159 - 2 5 7 5 ATÓM 762 N PHE 115 -7,831 35.323 51.153 1,000 2.32 Anisa 762 N PHE 115 2620 2062 3799 204 953 - 1 1 4 ATÓM 763 CA PHE 115 -7,115 34.026 51.183 1,000 2 2.69

SUBSTTTUTE SHEET (RULE 26)

W 99'33994

PCT / GH98O3860

ANISOU 763 CA PHE 115 2765 1909 3947 Press 109 3 - 1 8 - ATÓM 764 C PHE 115 -6,502 33 .754 49.816 1.000 -2-1 ». 4 9 Anisa 764 C PHE 115 2146 231Ó 3 702 305 559 - 2 5 5 ATÓM 765 0 PHE 115 -5,328 33.362 49.758 1,000 2 0.51 Anisa 765 0 PHE 115 2153 2011 3627 323 488 - 15 8 ATÓM 766 CB PHE 115 -8,096 32928 51.638 1,000 2 0.76 Anisa 766 C3 PHE 115 2369 1946 3574 -3 563 - 4 7 3 ATÓM 767 CG PHE 115 -7,496 31.590 51.998 1,000 2 0.23 Anisa 767 CG PHE 115 2369 1854 3463 -155 629 - 3 7 7 ATÓM 768 CD1 PHE 115 -6,915 30.756 51.041 1,000 2 0.35 Anisa 768 CD1 PHE 115 2572 1786 3372 -195 112 - 7 5 6 ATÓM 769 CD2 PHE 115 -7,474 31152 53.309 1,000 2 1.11 Anisa 769 CD2 PHE 115 2802 1932 3287 -113 17-6 8 9 ATÓM 770 CE1 PHE 115 -6,351 29.538 51325 1,000 2 1.09 Anisa 770 CE1 PHE 115 2502 1728 3784 -295 471 - 5 3 8 ATÓM 771 CE2 PHE 115 -6,938 29.901 53623 1,000 2 7.40 Anisa 771 CE2 PHE 115 5012 1955 3445 444 43-5 5 7 2 ATÓM 772 CZ PHE 115 -6,332 29.110 52.655 1,000 2 4.92 Anisa 772 CZ PHE 115 3356 1889 4222 50 1518 2 2 1 ATÓM 773 N GLU 116 -7,301 33768 48.757 1. 000 2 1.64 Anisa 773 N GLU 116 2396 1835 3990 338 261 - 1 3 ATÓM 774 CA GLU 116 -6,750 33.424 47.444 1,000 2 0.90 Anisa 774 CA GLU 116 2235 1965 3742 224 74 1 1 6 ATÓM 775 C GLU 116 -5,550 34.262 47054 1,000 2 0.32 Anisa 775 C GLU 116 1978 1899 3845 439 -108 4 4 8 ATÓM 776 0 GLU 116 -4,544 33.679 46.604 1,000 20:18 Anisa 776 0 GLU 116 2209 2147 3312 424 73 1 3! 9 ATÓM 777 CB GLU 116 -7,851 33.561 46.385 1,000 4.22 Anisa 777 CB GLU 116 2425 2638 4139 -467 -237 5 1 9 ATÓM 778 CG GLU 116 -7,339 33.331 44.980 1,000 3.27 Anisa 778 CG GLU 116 2425 2465 3952 -7 -495 7 5 i 0 ATÓM 779 CD GLU 116 -8,401 33.273 43.910 1,000 25.02 Anisa 779 CD GLU 116 2695 2703 4107 -510 -738 1 5 0 9 ATÓM 780 OEL GLU 116 -9,617 33.306 44.207 1,000 3 4.83 Anisa 780 OE1 GLU 116 2466 4606 6161 -203 -927 1 5 6 6 ATÓM 781 OE2 GLU 116 -8,001 33.030 42.763 1,000 4 0.92 Anisa 781 OE2 GLU 116 4389 7172 3988 -24 -968 6 9 3 ATÓM 782 N ARG 117 -5,549 35.571 47.300 1,000 2 0.60 Anisa 782 N ARG 117 2299 1811 3718 382 -10 4 6 9 ATÓM 783 CA ARG 117 -4,374 36.374 46.866 1,000 2 2.65 Anisa 783 CA ARG 117 2230 1791 4586 351 107 1 5 3 ATÓM 784 C ARG 117 -3,163 35.911 47.648 1,000 2 1.87 Anisa 784 C ARG 117 2269 1865 4178 252 179 9 7 ATÓM 785 0 ARG 117 -2,060 35.789 47.102 1,000 22:10 Anisa 785 0 ARG 117 2197 2270 3931 216 412 0 5 ATÓM 786 CB ARG 117 -4,682 37.861 47.105 1,000 9.47 Anisa 786 CB ARG 117 2849 1691 6658 259 -555 - 1 ATÓM 787 CG ARG 117 -3,485 38815 47.046 1,000 4 0.24 Anisa 787 CG ARG 117 3905 2567 8818 -819 -1330 -476 ATÓM 788 CD ARG 117 -3,745 40.160 47716 1,000 52.75 Anisa 788 CD ARG 117 4698 2848 12496 -595 -1653 - 1 6 7 9 ATÓM 789 NE ARG 117 -3,934 39.987 49.155 1,000 68.00 Anisa 789 NE ARG 117 8247 4719 12872 422 1842 - 3 4 4 1 ATÓM 790 CZ ARG 117 -3 · 166 40.448 50.126 1,000 8.38 Anisa 790 CZ ARG 117 13026 5658 11097 283 448 - 2 4 9 9 ATÓM 791 NH1 ARG 117 -2,097 41.186 49.849 1,000 8 9.01 Anisa 791 NH1 ARG 117 14218 11488 8115 -3,550 -6,761 3 5 6 7 ATÓM 792 NH2 ARG 117 -3,479 40.189 51.391 1,000 8 2.58 Anisa 792 NH2 ARG 117 16575 2856 11947 2617 2551 - 2 0 9 5 ATÓM 793 N ILE 118 -3,334 35.759 48.954 1. 000 2 1.70 Anisa 793 N ILE 118 2319 1797 4 127 311 271 - 3 14

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GU9S 03860

ATÓM 7 9 · ’. C A I L E 1 1 S -2 .2 06 35.425 49.8101.00020 99 Anisa 7 94 C A ILL Press 2 5 4 7 1624 3305 408 22i ~ 4 7 0 ATÓM 795 C IL 118 -1,596 34.073 49.475 1. 000 18.79 Anisa 795 C ILE 118 2222 1534 3384 21S 573 - 2 0 1 ATÓM 796 0 ILE 118 -0,409 33. 858 49.323 1. 000 17:27 Anisa 796 0 ILE 118 2194 1663 2707 283 351 - 13 6 ATÓM 797 CB ILE 118 -2 .588 35. 542 51.293 1. 000 2 2.62 Anisa 797 CB ILE 118 2702 1997 3 395 276 416 - 8 5 6 ATÓM 798 CG1 ILE 118 -2,916 36.995 5 L.700 1,000 7.54 Anisa 798 CG1 ILE 118 5077 1801 3 587 503 768 - 4 0 1 ATÓM 799 CG2 ILE 118 -1,552 34.940 52206 1. 000 3.59 Anisa 799 CG2 ILE 118 3084 2274 3 6 0 6 183 254 - 8 18 ATÓM 800 CD1 ILE 118 -3,493 37.115 53.096 1,000 9.35 Anisa 800 CD1 ILE 118 5212 2054 3 8 8 558 1114 - 6 4 5 ATÓM 801 N TRP 119 -2,454 33.069 4 9.3 1,000 17.93 Anisa 801 N TRP 119 2378 1605 2 82 8 147 -80 - 2 ’6 9 ATÓM 802 C A TRP 119 -2,035 31.688 4S.103 1,000 16:57 Anisa 802 C A TRP 119 2126 1538 2630 152 -25 - 1 6 ATÓM 803 C TRP 119 -1,575 31.476 47.676 1,000 16.98 Anisa 803 C TRP 119 2126 1723 2604 269 -91 - 5 1 ATÓM 804 0 TRP 119 -0,700 30.640 47.455 1,000 17:58 Anisa 804 0 TRP 119 1892 1674 3113 135 181 6 3 ATÓM 805 CB TRP 119 -3,127 30.690 49591 1,000 18:32 Anisa 805 CB TRP 119 2156 1789 3014 -34 5-7 ATÓM 806 CG TRP 119 -2,934 30.457 51.082 1,000 18:27 Anisa 806 CG TRP 119 2208 1711 3025 86,349 5 6 ATÓM 807 CD1 TRP 119 -3,354 31273 52.103 1,000 2 0.36 Anisa 807 CD1 TRP 119 2624 2029 3083 156 276 - 15 3 ATÓM 808 CD2 TRP 119 -2,213 29.383 51683 1,000 18.61 Anisa 808 CD2 TRP 119 2049 2055 2967 134 263 1 1 0 ATÓM 809 NE1 TRP 119 -2,955 30.773 53.323 1,000 2 0.55 Anisa 809 NE1 TRP 119 2471 2229 3109 93 266 - 1 0 6 ATÓM 810 CE2 TRP 119 -2,260 29.603 53073 1,000 2 0.21 Anisa 810 CE2 TRP 119 2529 2258 2893 180 754 2 9 7 ATÓM 811 CE3 TRP 119 -1,576 28.258 51.147 1,000 18:29 Anisa 811 CE3 TRP 119 2258 1714 2977 42 - 70 - 2 0 ATÓM 812 CZ2 TRP 119 -1,636 28.728 53 .981 1,000 2 1.97 Anisa 812 CZ2 TRP 119 2876 2526 2945 384 51-10 6 ATÓM 813 GB3 TRP 119 -0,968 27.375 52.045 1,000 19:35 Anisa 813 GB3 TRP 119 2576 2028 2750 187 415 2 9 9 ATÓM 814 CH2 TRP 119 -1,026 27618 53442 1,000 2 1.67 Anisa 814 CH2 TRP 119 3033 2379 2823 350 250 9 7 ATÓM 815 N THR 120 -2,129 32.192 46.701 1,000 16.93 Anisa 815 N THR 120 2023 1833 2577 122 -112 1 8 ATÓM 816 CA THR 120 -1,598 32.086 45.342 1,000 17.85 Anisa 816 CA THR 120 1915 2469 23S8 222 -371 - 3 2 4 ATÓM 817 C THR 120 -0,169 32587 45.288 1,000 17:15 Anisa 817 C THR 120 2031 1855 2629 241 -155 1 9 2 ATÓM 818 0 THR 120 0.700 31960 44.674 1,000 18.67 Anisa 818 0 THR 120 1996 1887 3212 389 -131 1 7 7 ATÓM 819 CB THR 120 -2,487 32.865 44.344 1,000 18:10 Anisa 819 CB THR 120 1951 2204 2720 28 -93,345 ATÓM 820 OG1 THR 120 -3,773 32238 44.284 1,000 2 0.49 Anisa 820 OG1 THR 120 1807 2801 3179 59 -363 558 ATÓM 821 CG2 THR 120 -1,919 32.803 42.933 1,000 2 2.46 Anisa 821 CG2 THR 120 2438 3266 2830 475 llá 7 0 5 ATÓM 822 N GLN 121 0094 33.708 45.956 1,000 18.62 Anisa 822 N GLN 121 2180 1657 3237 123 -94 2 1 3 ATÓM 823 CA GLN 121 1,466 34.232 45.993 1,000 18:15 Anisa 823 CA GLN 121 2077 1698 3119 77 96 5 2 0 ATÓM 824 C GLN 121 2.412 33 .284 46718 1. 000 4.17

SUBSTITUTE SHEET (RULE 26)

ΗΌ 99'33994

PCT / GB98 / 03860

ANISOU 824 C GLN 121 2022 143 1 3019 192 234 223 .atom 825 0 GLN 121 3.510 33047 46.270 1,000 «. 3 2 Anisa 825 0 GLN 121 1894 1800 3645 93 246 129 ATÓM 826 CB GLN 121 1.490 35.579 46.756 1. 000 2 2.90 Anisa 826 CB GLN 121 2520 1479 4702 327 -811 2 7 1 ATÓM 827 CG GLN 121 2. 888 36.159 46.871 1,000 2 7.04 Anisa 827 CG GLN 121 2949 2062 5262 -346 -400 132 ATÓM 828 CD GLN 121 3,530 36.511 45.535 1,000 3 1.94 Anisa 828 CD GLN 121 3307 2733 6097 983 1032 9 9 ATÓM 829 OE1 GLN 121 4. 660 36085 45247 1,000 6 2.76 Anisa 829 OE1 GLN 121 3009 9570 11267 1758 2365 2 0 2 9 ATÓM 830 NE2 GLN 121 2859 37.306 44716 1,000 5 5.89 Anisa 830 NE2 GLN 121 6516 7728 6993 2815 1744 3 2 4 9 ATÓM 831 N TYR 122 1,997 32791 47.871 1,000 16.87 Anisa 831 N TYR 122 2389 1518 2501 71 -161-5 5 4 ATÓM 832 CA TYR 122 2.795 31881 48683 1,000 17.97 Anisa 832 CA TYR 122 2564 1600 2666 176 -224 - 5 7 ATÓM 833 C TYR 122 3,080 30.600 47.909 1,000 16.83 Anisa 833 C TYR 122 1870 1460 3065 -31 -57 -98 ATÓM 834 0 TYR 122 4.224 30.129 47.823 1,000 17.67 Anisa 834 0 TYR 122 1891 1952 2872 189 -220 126 ATÓM 835 CB TYR 122 2.018 31.522 49.960 1,000 1.18 Anisa 835 CB TYR 122 2526 1821 2495 2 -325-5 5 ATÓM 836 CG TYR 122 2,753 30.619 50.898 1,000 17.89 Anisa 836 CG TYR 122 2332 1695 2769 255 -147-5 5 1 ATÓM 837 CD1 TYR 122 4.058 30.901 51.323 1,000 2 1.71 Anisa 837 CD1 TYR 122 2883 2101 3267 -257 -913 3 4 ATÓM 838 CD2 TYR 122 2.107 29.496 51.415 1,000 1.29 Anisa 838 CD2 TYR 122 2428 2026 3634 128 -267 468 ATÓM 839 CE1 TYR 122 4.680 30.037 52.212 1,000 1.27 Anisa 839 CE1 TYR 122 2681 2045 3356 140 -725 - 2 0 0 ATÓM 840 CE2 TYR 122 2.746 28.637 52.290 1,000 24.50 Anisa 840 CE2 TYR 122 3376 1876 4057 -292 -1163 506 ATÓM 841 CZ TYR 122 4043 28.914 52.675 1,000 22:16 Anisa 841 CZ TYR 122 3161 1881 3379 -909 - 1 2 8 ATÓM 842 OH TYR 122 4.699 28.079 53.566 1,000 23.72 Anisa 842 OH TYR 122 3471 2398 3142 52 -1005 - 5 7 ATÓM 843 N PHE 123 2.074 30.023 47.253 1,000 16:21 Anisa 843 N PHE 123 1794 1571 2793 49 -66 - 5 4 ATÓM 844 CA PHE 123 2347 28.843 46.397 1,000 15.71 Anisa 844 CA PHE 123 1622 1800 2548 34 -142 -1 0 3 ATÓM 845 C PHE 123 3,378 29.188 45337 1,000 15.96 Anisa 845 C PHE 123 1681 1304 3078 42 90 3 ATÓM 846 0 PHE 123 4276 28.375 45037 1,000 15:47 Anisa 846 0 PHE 123 1703 1437 2739 54 14 - 2 4 ATÓM 847 CB PHE 123 1,036 28.309 45.779 1,000 7.15 Anisa 847 CB PHE 123 1460 1364 2904 209 -148 1 ATÓM 848 CG PHE 123 1241 27.104 44.879 1,000 17:41 Anisa 848 CG PHE 123 2090 1620 2906 -39 -179 - 2 ATÓM 849 CD1 PHE 123 1.170 25.831 45.452 1,000 17:41 Anisa 849 CD1 PHE 123 1680 1439 3494 72 -119-2 2 5 5 ATÓM 850 CD2 PHE 123 1.490 27.259 43.513 1,000 18:22 Anisa 850 CD2 PHE 123 1723 2331 2870 -96 -216 - 3 7 2 ATÓM 851 CE1 PHE 123 1,419 24.740 44.636 1,000 19:15 Anisa 851 CE1 PHE 123 2112 1766 3397 212 -540 - 5 ATÓM 852 CE2 PHE 123 1.722 26.144 42.717 1,000 19.63 Anisa 852 CE2 PHE 123 1901 2476 3083 -134 -261-6 6 2 2 ATÓM 853 CZ PHE 123 1.635 24 .868 43.274 1,000 19:40 Anisa 853 CZ PHE 123 1525 2424 3421 385 -529 - 4 9 0 ATÓM 854 N ASP 124 3164 30.304 44.636 1. 000 16.86 Anisa 854 H ASP 124 1947 1466 2992 -23 -110 1 2 5

SUBSTTTUTE SHEET (RULE 26)

WO 99'33094

PCT / G 1) 98/03860

ATÓM S55 C.-. ASP 124 4. 060 30.640 43.544 1,000 1 7. S ľ Anisa S55 C A ASP 124 2103 1747 2 92 1 4 0 5 - ⁼ _2 J 3 14 ATÓM 856 C ASP 124 5.490 30.733 44024 1,000 17:52 Anisa 856 C ASP 124 1999 1439 3 2 19 181 94 8 9 ATÓM 857 0 ASP 124 6402 30.324 43.317 1,000 17:18 Anisa 857 0 ASP 124 2086 1427 3 015 34 ATÓM 858 CB AASP 124 3. 639 31.997 42.942 0534 2 1.77 Anisa 858 C3 AASP 124 3475 2089 2 ' ⁷ 0 6 642 -372 597 ATÓM 859 CC- AASP 124 4381 32.304 41.659 0534 19:28 Anisa 859 CG AASP 124 2376 1982 2 967 173 -553 495 ATÓM 860 OD1 AASP 124 4. 223 31.538 40.678 0534 2 1.03 Anisa 860 OD1 AASP 124 2189 2636 3164 -28 76 2 1 ATÓM 861 OD2 AASP 124 5068 33.348 4] .639 0534 2 4.96 Anisa 861 OD2 AASP 124 3681 2052 37 52 -296 -1067 889 ATÓM 862 C3 BASP 124 3632 31.975 42.908 0.466 19.67 Anisa 862 C3 BASP 124 2559 1993 2923 1003 673 446 ATÓM 863 CG BASP 124 2,368 31.849 42.089 0.466 2 2.78 Anisa 863 CG BASP 124 3552 3217 1889 872 178 117 5 ATÓM 864 OD1 BASP 124 2,021 30.781 41.545 0.466 7.78 Anisa 864 OD1 BASP 124 2138 3932 4483 100 503 347 ATÓM 865 OD2 BASP 124 1,703 32.893 41.902 0.466 9.73 Anisa 865 OD2 BASP 124 3845 3804 3646 1239 -312 16 4 5 ATÓM 866 N ARG 125 5669 31.416 45.153 1,000 16.65 Anisa 866 N ARG 125 1942 1350 3032 276 139 276 ATÓM 867 CA ARG 125 7.038 31.528 45.646 1,000 17:58 Anisa 867 C A ARG 125 1918 1819 2944 97 177 2 4 1 ATÓM 868 C ARG 125 7662 30.188 45.992 1,000 17:38 Anisa 868 C ARG 125 1544 1777 3282 -42 39 2 7 3 ATÓM 869 0 ARG 125 8841 29.942 45.754 1,000 18:26 Anisa 869 0 ARG 125 1639 1669 3631 -97 91 - 2 4 3 ATÓM 870 CB ARG 125 7.062 32.468 46.851 1,000 2 0.45 Anisa 870 CB ARG 125 2219 2162 3387 -244 450-2 7 4 ATÓM 871 CG ARG 125 6.860 33916 46.344 1,000 8.23 Anisa 871 CG ARG 125 3178 2007 5542 147 667 - 2 2 2 ATÓM 872 CD ARG 125 6.693 34.891 47.477 1,000 3 1.76 Anisa 872 CD ARG 125 3065 2279 6725 -628 1455-9 9 3 ATÓM 873 NE ARG 125 6496 36221 46.932 1,000 40.81 Anisa 873 NE ARG 125 3332 2095 10380 -169 1790 - 6 9 ATÓM 874 CZ ARG 125 5.970 37.229 47.628 1,000 4 3.42 Anisa 874 CZ ARG 125 4531 2891 9076 839 2072 - 1 7 8 ATÓM 875 NH1 ARG 125 5551 37.025 48.866 1,000 8.62 Anisa 875 NH1 ARG 125 3999 2858 78 16 -858 61 - 6 0 0 ATÓM 876 NH2 ARG 125 5858 38.382 47.006 1,000 4 2.11 Anisa 876 NH2 ARG 125 5319 2652 8030 908 1627 - 6 7 1 ATÓM 877 N GLN 126 6.884 29.282 46.557 1,000 15:28 Anisa 877 N GLN 126 1876 1527 2 4 04 -70 13-60 ATÓM 878 C A GLN 126 7.376 27,929 46853 1,000 15:37 Anisa 878 CA GLN 126 1726 1625 2488 -54 -312 2 0 ATÓM 879 C GLN 126 7649 27.150 45. 578 1,000 14:21 Anisa 879 C GLN 126 1643 1268 2 4 88 -75 -397 7 1 ATÓM 880 0 GLN 126 8682 26.462 45 .496 1,000 15:36 Anisa 880 0 GLN 126 1531 1554 2 7 5 -37 -316 5 3 ATÓM 881 CB GLN 126 6356 27.158 47 702 1,000 17:40 Anisa 881 CB GLN 126 2034 1313 3264 158 293 4 3 ATÓM 882 CG GLN 126 6336 27.634 49 150 1,000 6.14 Anisa 882 CG GLN 126 4503 1690 3 73 9 431 1908 - 7 2 2 ATÓM 883 CD GLN 126 5208 26.998 49.891 1,000 2 1.95 Anisa 883 CD GLN 126 2957 2670 2713 0 -123 ATÓM 884 OE1 GLN 126 4051 27.372 49.730 1,000 4 2.52 Anisa 884 OE1 GLN 126 2994 5747 7416 -62 -1272 3147 ATÓM 885 NE2 GLN 126 5 .524 26.003 50.691 1. 000 8.32

SUBSTTTUTE SHEET (RULE 26) w Ο 99'33994

PCT / GB9S / 03860

Anisa 885 ΝΞ2 GLN 12 6 2867 3 97 1 3922 - 184 -760 1 3 1 1 ATÓM 886 N TYR 127 6. 797 27.287 44574 1,000 »5 2 Anisa 886 N TYR 127 1629 1438 2448 -41 -373-3 6 ATÓM 887 C A TYR 127 7.039 26.554 43.317 1. 000 1 3.9 Anisa 887 C A TYR 127 1563 1455 2277 -136 -234 150 ATÓM 888 C TYR 127 8289 27091 42.624 1 .000 1 4.5 4 Anisa 888 C TYR 127 1461 1318 2745 24 -195 190 ATÓM 889 0 TYR 127 9.133 26.345 42.140 1.000 1 4.3 9 Anisa 889 0 TYR 127 1611 1580 2277 34 -259 9 ATÓM 890 CB TYR 127 5.801 26.676 42.435 1. 000 1 4.0 0 Anisa 890 CB TYR 127 1510 1549 2258 29 -180-7 0 ATÓM 891 CG TYR 127 5752 25.795 41.202 1.000 1 2.3 3 Anisa 891 CG TYR 127 1315 1037 2334 -34 -184 4 5 ATÓM 892 CD1 TYR 127 6483 24626 41024 1,000 1 4.0 5 Anisa 892 CD1 TYR 127 1810 1158 2371 7 -84-8 ATÓM 893 CD2 TYR 127 4.837 26.086 40.206 1,000 1 5.7 1 Anisa 893 CD2 TYR 127 1936 1548 2484 55 -512 2 1 ATÓM 894 CE1 TYR 127 6382 23.829 39899 1.000 13.10 Anisa 894 CE1 TYR 127 1450 999 2529 -101 -227 - 6 2 ATÓM 895 CE2 TYR 127 4661 25.322 39.071 1,000 1 5.07 Anisa 895 CE2 TYR 127 1928 1620 2177 158 -344 1 9 7 ATÓM 896 CZ TYR 127 5.440 24.179 38.934 1.000 13.71 Anisa 896 CZ TYR 127 1617 1348 2245 -146 -106 2 5 6 ATÓM 897 OH TYR 127 5.337 23386 37.811 1,000 1 5.0 4 Anisa 897 OH TYR 127 1682 1755 2279 -87 -60 ATÓM 898 N THR 128 8467 28.412 42.616 1.000 14.69 Anisa 898 N THR 128 1813 1324 2446 -154 -217 268 ATÓM 899 CA THR 128 9.673 28.984 42.011 1.000 14.67 Anisa 899 CA THR 128 1867 1469 2238 -98 -32 ATÓM 900 C THR 128 10.921 28.552 42.736 1.000 14.68 Anisa 900 C THR 128 1794 1318 2466 59 - 123 - 2 8 5 ATÓM 901 0 THR 128 11.900 28166 42062 1,000 1 5.4 5 Anisa 901 0 THR 128 1715 1487 2667 -258 153 7 1 ATÓM 902 CB THR 128 9572 30.544 42.069 1.000 16.02 Anisa 902 CB THR 128 2043 1348 2695 -78 59 4 7 9 ATÓM 903 OGL THR 128 8.519 30.849 41162 1.000 19.14 Anisa 903 OG1 THR 128 2226 2038 3008 195 -23,545 ATÓM 904 CG2 THR 128 10.835 31.187 41.582 1,000 1 9.0 3 Anisa 904 CG2 THR 128 2107 1329 3793 125,311 6 1 8 ATÓM 905 N ALA 129 10.933 28.564 44.085 1.000 1 4.2 1 Anisa 905 N ALA 129 1708 1266 2424 -137 -256 -1 8 1 ATÓM 906 CA ALA 129 12.108 28.110 44836 1.000 15.08 Anisa 906 CA ALA 129 1670 1435 2624 -118 -210 - ATÓM 907 C ALA 129 12.389 26.643 44.562 1.000 14.37 Anisa 907 C ALA 129 1706 1299 2457 -159 -203 ATÓM 908 0 ALA 129 13.552 26.238 44.445 1.000 14.10 Anisa 908 0 ALA 129 1758 1464 2137 -5 -244 - ATÓM 909 CB ALA 129 11.887 28.313 46.313 1.000 17.08 Anisa 909 CB ALA 129 2132 1851 2506 -183 -514 - 2 4 9 ATÓM 910 N SER 130 11.343 25.819 44.553 1.000 1 4.1 8 Anisa 910 N SER 130 1884 1237 2267 -224 -257 1 7 4 ATÓM 911 CA SER 130 11.487 24.375 44.351 1.000 15.44 Anisa 911 CA SER 130 1840 1219 2807 -115 -135-7 ATÓM 912 C SER 130 12.072 24.114 42.965 1.000 14.45 Anisa 912 C SER 130 1345 1481 2665 78 - 796 - 2 0 9 ATÓM 913 0 SER 130 13.037 23.329 42.807 1.000 1 4.4 3 Anisa 913 0 SER 130 1327 1382 2773 -74 -246 ATÓM 914 CB SER 130 10.120 23.677 44.663 1.000 17.54 Anisa 914 CB SER 130 1555 1225 3884 -379 -647 ATÓM 915 OG SER 130 9.268 23.888 43.558 1.000 27.32 Anisa 915 OG SER 130 2321 3 168 4 893 11 -1207 865

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ATÓM 9 16 N ARG 131 11.555 - 43 - 24 772 L.90 14.47 Anisa 916 N ARG 131 1421 1448 2628 151 - 1 ó 6 ATÓM 917 C A ARG 131 12.163 24 .598 40.592 i. 000 14-91 Anisa 917 C A ARG 131 1689 1452 2525 -4 (526) - 3 4 1 ATÓM 918 C ARG 131 13.605 25.079 4 0.5 1. 000 5.14 Anisa 918 C ARG 131 1772 1435 2132 -72 -381 - 1 7 3 ATÓM 919 ABOUT ARG 131 14. 44S 24.438 39.912 1. 000 15:14 Anisa 919 ABOUT ARG 131 1829 1658 2267 -109 -170 - 2 3 0 ATÓM 920 CB ARG 131 11.349 25.316 39.514 1. 000 15.77 Anisa 920 CB ARG 131 1720 1613 2650 -54 -493 - 9 4 ATÓM 921 CG ARG 131 9. 970 24.737 39.251 1. 000 8.16 Anisa 921 CG ARG 131 1703 1695 27 L1 -13 -647 - 14 1 ATÓM 922 CD ARG 131 9.326 25.390 38.017 1,000 6.56 Anisa 922 CD ARG 131 3589 2689 3 813 -1037 -2,156 7 4 5 ATÓM 923 NE ARG 131 9.327 26.831 37.918 1,000 2 5.91 Anisa 923 NE ARG 131 2856 2814 417 4 -979 -1,682 14 13 ATÓM 924 CZ ARG 131 8472 27.716 38.413 1,000 3 1.86 Anisa 924 CZ ARG 131 3546 2861 5697 -254 -1094 2 2 0 1 ATÓM 925 NH1 ARG 131 7467 27244 39 138 1,000 3 1.34 Anisa 925 NH1 ARG 131 5127 3636 314 4 -1474 -458 - 115 ATÓM 926 NH2 ARG 131 8.633 29.032 38.235 1,000 0.12 Anisa 926 NH2 ARG 131 3500 2831 8912 -582 -1620 18 0 2 ATÓM 927 N ALA 132 13.893 26.186 41236 1,000 13:42 Anisa 927 N ALA 132 1683 1385 2033 -85 -652 - 2 4 ATÓM 928 CA ALA 132 15.246 26.751 41128 1,000 13:38 Anisa 928 CA ALA 132 1617 1443 202 2 -16 -499 - 7 9 ATÓM 929 C ALA 132 16.225 25.808 41837 1,000 13:37 Anisa 929 C ALA 132 1398 1365 233 6 -93 -253 1 5 4 ATÓM 930 0 ALA 132 17.306 25.586 41328 1,000 14:43 Anisa 930 ABOUT ALA 132 1459 1772 22 51 -91 -240 1 0 6 ATÓM 931 CB ALA 132 15.275 28084 41.859 1,000 16:52 Anisa 931 CB ALA 132 2019 1243 3014 -199 -366 - 2 3 6 ATÓM 932 N VAL 133 15.893 25.248 42.996 1,000 13.62 Anisa 932 N VAL 133 1522 1515 2139 -63 -362 8 6 ATÓM 933 CA VAL 133 16.839 24.363 43.689 1,000 14.86 Anisa 933 C A VAL 133 1902 1566 2179 120 -491 - 2 7 ATÓM 934 C VAL 133 16.923 23.073 42.890 1,000 4.15 Anisa 934 C VAL 133 1390 1633 2690 -9 -220 -2 2 8 ATÓM 935 0 VAL 133 18.036 22.538 42.773 1,000 15:49 Anisa 935 ABOUT VAL 133 1442 1814 2630 63 -193-9 9 ATÓM 936 CB VAL 133 16.545 24.170 45.187 1,000 14.61 Anisa 936 CB VAL 133 1528 1789 2234 -45 -391 2 1 0 ATÓM 937 CG1 VAL 133 15.362 23.267 45.453 1,000 16.78 Anisa 937 CG1 VAL 133 1544 2123 2708 -249 -437 - 8 1 ATÓM 938 CG2 VAL 133 17.766 23.650 45,950 1,000 16:51 Anisa 938 CG2 VAL 133 1769 1942 2561 -61 -831 6 4 ATÓM 939 N ALA 134 15.840 22.583 42.270 1,000 13.73 Anisa 939 N ALA 134 1605 1451 2160 -75 -397 1 8 5 ATÓM 940 CA ALA 134 15.951 21.369 41.451 1,000 14:21 Anisa 940 CA ALA 134 1505 1796 2100 116 -570 - 3 3 ATÓM 941 C ALA 134 16.838 21.618 40246 1,000 7.15 Anisa 941 C ALA 134 1766 1511 2450 43 -292 1 6 ATÓM 942 ABOUT ALA 134 17.600 20.750 39.800 1,000 14:36 Anisa 942 ABOUT ALA 134 1555 1567 2333 -60 -286 5 2 ATÓM 943 CB ALA 134 14. 535 20.925 41.032 1,000 16.97 Anisa 943 CB ALA 134 1472 1943 3031 12 -470 2 9 9 ATÓM 944 N ARG 135 16.752 22.808 39.631 1,000 15:48 Anisa 944 N ARG 135 1848 1600 2433 14 -341-2 ATÓM 945 C A ARG 135 17.618 23.153 38508 1,000 7.16 Anisa 945 CA ARG 135 2139 1230 2735 -138 -189 3 5 ATÓM 946 C ARG 135 19.082 23.057 38.955 1. 000 15.70

SUBSTTTUTE SHEET (RULE 26)

WO 94'33994

PCT / Gn9S / 03860

ANI SAL 94 6 C ARG 135 2059 1370 2535 -134 27121 ATÓM 947 0 ARG 135 19 Dec 928 22.604 38.176 1. 000 W 07 Anisa 947 0 ARG 135 2317 2014 2534 108 256 2 7 ó ATÓM 948 CB ARG 135 17.277 24.585 38 .096 I. 000 2 1.96 Anisa 948 CB ARG 135 3936 1640 2767 -4 1414 614 ATÓM 949 CG ARG 135 17.571 24.989 36. 689 1,000 7.53 Anisa 949 CG ARG 135 5112 2482 2866 816 -610 595 ATÓM 950 CD ARG 135 16.930 26.332 36393 1,000 3.27 Anisa 950 CD ARG 135 3548 2428 2865 148 60 13 7 1 ATÓM 951 NE ARG 135 15.551 26.309 35928 1,000 2 2.68 Anisa 951 NE ARG 135 3488 1575 3556 -116 167 297 ATÓM 952 CZ ARG 135 14. 520 26.858 36.562 1,000 2 5.90 Anisa 952 CZ ARG 135 3801 2165 3874 921 -506-1 7 9 ATÓM 953 NH1 ARG 135 14.708 27.515 37.702 1,000 2 3.50 Anisa 953 NH1 ARG 135 3582 2378 2969 94,137,532 ATÓM 954 NH2 ARG 135 13.287 26.758 36.035 1,000 4.30 Anisa 954 NH2 ARG 135 3520 2441 3272 -101 73 5 8 2 ATÓM 955 N GLU 136 19.403 23. 533 40.149 1,000 15.76 Anisa 955 N GLU 136 1897 1696 2396 -178 17 3 18 ATÓM 956 CA GLU 136 20.752 23.431 40694 1,000 15:16 Anisa 956 CA GLU 136 1687 1770 2302 -97 279 140 ATÓM 957 C GLU 136 21.186 22.001 40.978 1,000 16.74 Anisa 957 C GLU 136 1535 1704 3122 -148 -172-7 2 ATÓM 958 0 GLU 136 22.350 21.637 40.701 1,000 17:42 Anisa 958 0 GLU 136 1710 1908 2999 7 30 9 2 ATÓM 959 CB GLU 136 20.957 24.284 41.962 1,000 16.64 Anisa 959 CB GLU 136 2048 1785 2487 53 11 -16 ATÓM 960 CG GLU 136 20.762 25.772 41.718 1,000 17.80 Anisa 960 CG GLU 136 2036 1714 3014 -286 -169 110 ATÓM 961 CD GLU 136 21534 26.269 40.513 1,000 2 0.92 Anisa 961 CD GLU 136 2174 2273 3503 -343 69 4 6 9 ATÓM 962 OE1 GLU 136 22.742 25.987 40.454 1,000 2 4.97 Anisa 962 OEL GLU 136 2116 2434 4938 -494 531 219 ATÓM 963 OE2 GLU 136 21.022 27037 39672 1,000 4.77 Anisa 963 0E2 GLU 136 2975 2618 3817 -708 -133 1 0 2 8 ATÓM 964 N VAL 137 20.262 21.172 41.450 1,000 15:34 Anisa 964 N VAL 137 1681 1696 2453 -108 -286 1 1 3 ATÓM 965 CA VAL 137 20568 19.750 41647 1,000 15.92 Anisa 965 CA VAL 137 1755 1802 2493 83 -4 2 10 ATÓM 966 C VAL 137 20.926 19.086 40326 1,000 15.86 Anisa 966 C VAL 137 1604 1869 2555 -38 -35 6 6 ATÓM 967 0 VAL 137 21.905 18.308 40.174 1,000 16.70 Anisa 967 0 VAL 137 1617 2118 2609 72 -151-9 0 ATÓM 968 CB VAL 137 19.358 18.990 42283 1,000 15:35 Anisa 968 CB VAL 137 1729 1663 2440 8 -29 5 ATÓM 969 CG1 VAL 137 19.607 17.478 42.176 1,000 16.93 Anisa 969 CG1 VAL 137 1521 1689 3223 160 -345 9 6 ATÓM 970 CG2 VAL 137 19.144 19.420 43.724 1,000 15:43 Anisa 970 CG2 VAL 137 1529 2090 2245 -53 -277 185 ATÓM 971 N LEU 138 20.149 19.407 39.284 1,000 15:52 Anisa 971 N LEU 138 1625 1735 2535 -105 -61 109 ATÓM 972 C A LEU 138 20.378 18.881 37.936 1,000 15.74 Anisa 972 CA LEU 138 1576 1862 2543 -71 15 5 1 ATÓM 973 C LEU 138 21.721 19.396 37.406 1,000 17:42 Anisa 973 C LEU 133 1588 2119 2912 -87 162-4 5 ATÓM 974 0 LEU 138 22.503 18.609 36.846 1,000 19:13 Anisa 974 0 LEU 138 1878 2406 2985 186 317 6 2 ATÓM 975 CB LEU 138 19.211 19.248 36.996 1,000 14.70 Anisa 975 CB LEU 138 1592 1642 2349 -50 141 190 ATÓM 976 CG LEU 138 17.883 18.541 37.375 1,000 1 4 .3 e A1JISOU 976 CG LEU 138 1657 1409 2399 -44 -4 2 8 7

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PC I7G Β98Ό3860

ATÓM 977 CD1 LEU 13 7 16.77-1 ANISO'J 977 CD1 LEU 138 1743 ATÓM 978 CD2 LEU 138 17.975 Anisa 978 CD2 LEU 138 2185 ATÓM 979 N ARG 139 21.963 Anisa 979 N ARG 139 1797 ATÓM 980 CA ARG 139 23.189 Anisa 980 CA ARG 139 2043 ATÓM 981 C ARG 139 24.419 Anisa 981 C ARG 139 1797 ATÓM 982 0 ARG 139 25.461 Anisa 982 0 ARG 139 2046 ATÓM 983 CB ARG 139 23,152 Anisa 983 CB ARG 139 2525 ATÓM 984 CG ARG 139 23.886 Anisa 984 CG ARG 139 6517 ATÓM 985 CD ARG 139 23.852 Anisa 985 CD ARG 139 7459 ATÓM 986 NE ARG 139 22.525 Anisa 986 NE ARG 139 6637 ATÓM 987 CZ ARG 139 21.821 Anisa 987 CZ ARG 139 5939 ATÓM 988 NH1 ARG 139 22.308 Anisa 988 NH1 ARG 139 6564 ATÓM 989 NH2 ARG 139 20.614 Anisa 989 NH2 ARG 139 6162 ATÓM 990 N ALA 140 24.357 Anisa 990 N ALA 140 1742 ATÓM 991 CA ALA 140 25.532 Anisa 991 CA ALA 140 1583 ATÓM 992 C ALA 140 25.932 Anisa 992 C ALA 140 2018 ATÓM 993 0 ALA 140 27.109 Anisa 993 0 ALA 140 1900 ATÓM 994 CB ALA 140 25.273 Anisa 994 CB ALA 140 1824 ATÓM 995 N THR 141 24.958 Anisa 995 N THR 141 2014 ATÓM 996 CA THR 141 25.151 Anisa 996 C A THR 141 1870 ATÓM 997 C THR 141 25.269 Anisa 997 C THR 141 1492 ATÓM 998 0 THR 141 25.343 Anisa 998 0 THR 141 1871 ATÓM 999 CB THR 141 24.048 Anisa 999 CB THR 141 1708 ATÓM 1000 OG1 THR 141 22.788 Anisa 1000 OG1 THR 141 1894 ATÓM 1001 CG2 THR 141 23982 Anisa 1001 CG2 THR 141 1521 ATÓM 1002 N GLY 142 25.361 Anisa 1002 N GLY 142 2091 ATÓM 1003 CA GLY 142 25.517 Anisa 1003 CA GLY 142 1878 ATÓM 1004 C GLY 142 24.284 Anisa 1004 C GLY 142 1972 ATÓM 1005 0 GLY 142 24443 Anisa 1005 0 GLY 142 2432 ATÓM 1006 N THR 143 23.093 Anisa 1006 W THR 143 1895 ATÓM 1007 CA THR 143 21.909

-45 - 19.122 3 ó. 4 9 i 1. coo 16:13 1848 2539 12S - • i i S 1 0 8 17.027 37156 1. 000 17:48 1435 3021 -107 -4SO 2 8 7 20.708 37.548 1. 000 17:44 2157 2674 -319 238 1 9 2 21.319 36.996 1. 000 5.19 2462 2735 -366 482 376 20.734 37.685 1. 000 19.72 2600 3097 -518 482 376 20.432 37.094 1,000 2 0.70 2469 3350 -288 607 195 22.850 37.101 1,000 4.54 2403 4395 -402 951 590 23.665 36.073 1,000 6.05 2967 4 212 -2176 1609 140 25.148 36.443 1,000 4 4.95 1902 7716 -242 -1323 1 9 3 0 25.727 36,547 1,000 3.27 3846 5959 -828 -2173 - 6 9 8 26.330 35.605 1,000 4 1.34 4102 5 6 6 7 497 644 1 1 4 0 26.436 34.376 1. 000 4 4.01 4146 6011 550 1393 336 26837 35.833 1,000 4 5.75 4618 6602 537 1938 2 3 0 5 20.566 39.009 1,000 18.77 2387 3003 -255 145 6 9 20.169 39.773 1,000 19:53 2641 3197 -28 39 - 6 6 8 18.732 39.490 1,000 18.96 2342 2843 -67 76 - 1 O 3 18.335 39626 1,000 2 1.36 2436 3778 -2 472-8 0 20.345 41.275 1,000 19.74 2592 3084 35 0 -360 17.943 39.062 1,000 2 0.32 2209 3498 -115 305 - 1 2 8 16.530 38.717 1,000 17:15 2039 2609 61 51 2 18 16.278 37.208 1,000 17:44 2443 2693 21 278 199 15.106 36.792 1,000 19:24 2623 2814 63 576 - 6 3 15.629 39.290 1,000 16.79 2261 2410 82 164 3 1 16.012 38.710 1,000 17:18 2235 2399 -101 -53 518 15.734 40.807 1,000 17.83 2878 2377 164 -43 2 0 17.301 36.381 1,000 19.69 2789 2603 -708 302 297 17.123 34.923 1,000 8.19 2819 2551 128 -163 255 16.441 34.313 1,000 18.75 2410 2744 0 252-1 1 7 15.755 33.315 1,000 2 2.41 2681 3403 -161 571 - 6 7 0 16.650 34.854 1,000 17:28 2002 2667 67 300 244 15.932 34.393 1,000 16.88

SUBSTTTUTE SHEET (RULE 26)

WO 99'33994

PCT / GB98'03860

Anisa 1007 C A THR 14 3 1953 2006 2456 164 3 31 6 6 ATÓM 1003 C THR 143 20.998 16.660 33432 1,000 1 * 7 *. Ό 2 Anisa 1008 C THR 143 2149 1795 2521 82 195 1 1 7 ATÓM 1009 ABOUT THR 143 20.457 17.713 33 .764 1,000 2 0.30 Anisa 1009 0 THR 143 2795 1815 3103 344 12-28 ATÓM 1010 CB THR 143 21.085 15.490 35623 1,000 16:40 Anisa 1010 CB THR 143 1755 2329 2148 -37 95-44 ATÓM 1011 OG1 THR 143 21. 922 14.692 36.479 1,000 17.82 Anisa 1011 OG1 THR 143 2009 2075 2688 -109 38 3 3 7 ATÓM 1012 CG2 THR 143 19.887 14.621 35.270 1,000 19:51 Anisa 1012 CG2 THR 143 1957 2290 3167 -192 -94 100 ATÓM 1013 N GLU 144 20.742 16.070 32.248 1,000 18.79 Anisa 1013 N GLU 144 2138 2203 2800 47 12 -12 1 ATÓM 1014 C A GLU 144 19.729 16.573 31334 1,000 2 0.13 Anisa 1014 C A GLU 144 2202 2696 2750 -292 -41 316 ATÓM 1015 C GLU 144 18.637 15.506 31.254 1,000 19:18 Anisa 1015 C GLU 144 2255 2614 2418 -292 230 - 1 2 1 ATÓM 1016 0 GLU 144 18. 827 14.438 30.665 1,000 2 1.46 Anisa 1016 0 GLU 144 2268 2442 3446 19 648 - 8 8 ATÓM 1017 CB aglut 144 20.250 17.061 30.006 0753 2 9.50 Anisa 1017 CB aglut 144 3376 4266 3566 -855 205 1 5 0 1 ATÓM 1018 CG aglut 144 20.195 18.567 29.741 0753 6.54 Anisa 1018 CG aglut 144 6059 3913 3913 -1728 1769 795 ATÓM 1019 CD aglut 144 21.242 19.411 30.426 0753 3 3.13 Anisa 1019 CD aglut 144 4189 3432 4966 104 744 884 ATÓM 1020 OE1AGLU 144 21.079 19.690 31.641 0753 5 1.91 Anisa 1020 OE1AGLU 144 3684 11101 4940 -868 -202 - 5 9 0 ATÓM 1021 OE2AGLU 144 22.207 19.910 29.807 0753 5 0.79 Anisa 1021 OE2AGLU 144 7949 3695 7,653 -3,071 3099 - 1 2 ATÓM 1022 CB BGLU 144 20.372 16.724 29.951 0247 18:36 Anisa 1022 CB BGLU 144 868 3091 3016 334 2 6 2 ATÓM 1023 CG BGLU 144 21.214 17.988 29.779 0247 3.54 Anisa 1023 CG BGLU 144 1301 3586 4056 -38 595 558 ATÓM 1024 CD BGLU 144 21.150 18.468 28.336 0247 3.24 Anisa 1024 CD BGLU 144 3589 3975 5064 438 -20 2 0 3 0 ATÓM 1025 OE1BGLU 144 20.417 17.818 27.557 0247 8.68 Anisa 1025 OE1BGLU 144 3222 4813 2861 389 1730 1 2 8 0 ATÓM 1026 OE2BGLU 144 21.814 19.464 27.990 0247 5.35 Anisa 1026 OE2BGLU 144 3176 5148 5108 36 1752 1 5 1 6 ATÓM 1027 N PRO 145 17.508 15.724 31911 1,000 17:11 Anisa 1027 N PRO 145 2132 1825 2543 68 62 15 8 ATÓM 1028 CA PRO 145 16.396 14.781 31.846 1,000 17:41 Anisa 1028 CA PRO 145 2290 1942 2384 -73 400 1 2 ATÓM 1029 C PRO 145 15.966 14.546 30.406 1,000 17.94 Anisa 1029 C PRO 145 2386 1955 2475 -116 292 - 1 0 3 ATÓM 1030 ABOUT PRO 145 16.068 15.439 29.557 1,000 18:26 Anisa 1030 0 PRO 145 2271 2196 2472 -272 170 4 5 ATÓM 1031 CB PRO 145 15.250 15.493 32594 1,000 7.17 Anisa 1031 CB PRO 145 2181 1771 2534 34 133 - 1 4 3 ATÓM 1032 CG PRO 145 15.950 16.504 33.464 1,000 17:11 Anisa 1032 CG PRO 145 2341 1841 2319 23 -49-2 2 4 ATÓM 1033 CD PRO 145 17.131 16.977 32.649 1,000 17:54 Anisa 1033 CD PRO 145 2178 1601 2884 178 -88 303 ATÓM 1034 N ASP 146 15.490 13.346 30.104 1,000 18:15 Anisa 1034 N ASP 146 2140 1965 2790 -60 321-1 5 2 ATÓM 1035 C A ASP 146 14.909 13.121 28.775 1,000 18:43 Anisa 1035 C A ASP 146 2487 1664 2853 -329 310-15 6 ATÓM 1036 C ASP 146 13.809 14.154 28.566 1,000 7.18 Anisa 1036 C ASP 146 2824 1979 2064 -31 208 - 3 0 8 ATÓM 1037 ABOUT ASP 146 12.959 14.333 29.422 1. 000 18:29 Anisa 1037 0 ASP 146 2 4 9 1 2173 2287 -168 203 -230

SUBSTThe SHEET (RULE 26)

WO 99/33994

PCV / GBOS'03860

ATÓM 1038 CB ASP 146 14.221 - 47 - 11.735 23.717 1,000 2 3.50 Anisa 1038 CB ASP 146 3489 1671 3 7 6 9 -652 9Όβ * - ó 6 5 ATÓM 1039 CG ASP 146 13.636 11.508 27.334 1,000 4.15 Anisa 1039 CG ASP 146 4070 4205 4700 -1004 3m - 2 3 8 ATÓM 1040 OD1 ASP 146 12.393 11.521 27.138 1.000 4.73 Anisa 1040 OD1 ASP 146 3 971 9175 3849 -2156 SS3 378 ATÓM 1041 OD2 ASP 146 14.421 11.229 26.397 1.000 4.78 Anisa 1041 OD2 ASP 146 4342 8626 4 0 4 7 - 813 289 - 2 4 2 ATÓM 1042 N GLY 147 13.901 14.854 27,450 1,000 19:28 Anisa 1042 N GLY 147 2622 2331 2 3''4 -63 4 -72 113 ATÓM 1043 C A GLY 147 12.916 15.878 27.171 1.000 18:58 Anisa 1043 CA GLY 147 2463 2607 1991 -550 -234 - 3 7 ATÓM 1044 C GLY 147 13.355 17.262 27.590 1.000 18:25 Anisa 1044 C GLY 147 2511 2432 1993 -335 -138 6 4 ATÓM 1045 0 GLY 147 12.586 18.183 27.289 1.000 2 0.74 Anisa 1045 0 GLY 147 2469 2739 2673 -182 -144 2 0 5 ATÓM in 1046 N GLY 148 14.494 17.357 28.286 1.000 17:38 Anisa in 1046 N GLY 148 2237 2174 2191 -462 -42-9 0 ATÓM 1047 C A GLY 148 15.027 18.658 28.672 1.000 16.72 Anisa 1047 CA GLY 148 2308 1789 2255 39 -82 ! - 7 7 ATÓM 1048 C GLY 148 14.653 19.076 30.085 1.000 13.94 Anisa 1048 C GLY 148 1517 1645 2136 77 -201 117 ATÓM 1049 0 GLY 148 13.637 18.634 30.694 1.000 16:29 Anisa 1049 0 GLY 148 1839 1863 2487 -151 -77 285 ATÓM 1050 N VAL 149 15,431 20.003 30.641 1.000 14.93 Anisa 1050 N VAL 149 1624 1780 2269 1 -193 - 1 4 ATÓM in 1051 CA VAL 149 15.275 20.509 32.017 1.000 14:16 Anisa in 1051 CA VAL 149 1647 1511 2223 92 -195 8 6 ATÓM 1052 C VAL 149 13.958 21.218 32.235 1.000 14:37 Anisa 1052 C VAL 149 1735 1044 2682 -39 83188 ATÓM 1053 0 VAL 149 13.203 20.970 33.163 1.000 14.63 Anisa 1053 0 VAL 149 1653 1517 2390 -160 -40 10 7 ATÓM 1054 CB VAL 149 16.439 21.410 32.417 1.000 2.14 Anisa 1054 CB VAL 149 1745 1530 2052 -112 -57 270 ATÓM 1055 CG1 VAL 149 16.228 22.101 33.752 1.000 16:48 Anisa 1055 CG1 VAL 149 2360 1709 2193 -153 -306 8 7 ATÓM 1056 CG2 VAL 149 17.733 20.614 32.482 1.000 17.85 Anisa 1056 CG2 VAL 149 1618 1937 3226 -59 -52 441 ATÓM 1,057 N GLU 150 13.634 22.199 31.371 1.000 15:26 Anisa 1,057 N GLU 150 1759 1328 2711 186 37 2 6 7 ATÓM 1058 CA GLU 150 12.471 23.028 31.687 1.000 14.91 Anisa 1058 CA GLU 150 1591 1434 2641 93 13 4 15 ATÓM 1059 C GLU 150 11.182 22.237 31.553 1.000 16.66 Anisa 1059 C GLU 150 1680 1980 2670 -197 113 199 ATÓM 1060 0 GLU 150 10.259 22.408 32.379 1.000 15.89 Anisa 1060 0 GLU 150 1697 1761 2579 29 79 5 8 0 ATÓM 1061 CB GLU 150 12.531 24.305 30.874 1.000 7.17 Anisa 1061 CB GLU 150 1925 1337 3223 254 189 513 ATÓM 1062 CG GLU 150 13.761 25167 31.220 1.000 19:00 Anisa 1062 CG GLU 150 2483 1212 3523 -65 -95 465 ATÓM 1063 CD GLU 150 13.810 25.624 32.658 1.000 2 0.32 Anisa 1063 CD GLU 150 2444 1746 3532 -130 -24 454 ATÓM 1064 ΟΞ1 GLU 150 12.781 25.749 33.377 1.000 2 0.88 Anisa 1064 OE1 GLU 150 2558 1728 3648 28 58 3 9 6 ATÓM 1065 OE2 GLU 150 14.913 25.946 33.161 1.000 2 1.77 Anisa 1065 OE2 GLU 150 2549 2030 3693 -165 -202 273 ATÓM 1066 N ALA 151 11.050 21.288 30.603 1.000 14.98 Anisa 1066 N ALA 151 1649 1710 2333 37 -307 551 ATÓM 1067 CA ALA 151 9834 20.475 30.543 1.000 15.79 Anisa 1067 C A ALA 151 1820 2045 2136 -173 -198 408 ATÓM 1068 C ALA 151 9748 19.531 31.724 1.000 i 15.38

SUBSTTTUTE SHEET (RULE 26)

WO 99/33094

PCT / G B9S / 03860

Anisa 1068 C ALA 151 1674 1953 2216 16 5 1S 1 4 4 2 ATÓM 1069 0 ALA 151 8.642 19.186 32.184 1,000 5 1 Anisa 1069 0 ALA 151 1778 1852 2643 -152 110 3 3 0 ATÓM 1070 CB ALA 151 9,823 19.663 29236 í. 000 1 8. 0 5 Anisa 1070 CB ALA 151 1910 2811 2139 -275 -316 165 ATÓM 1071 N PHE 152 10.893 19.135 32.306 1,000 1 4. 2 5 Anisa 1071 N PHE 152 1858 1132 2423 10 -107 2 ! 6 3 ATÓM 1072 C A PHE 152 10.893 18.285 33.493 1,000 1 3. 4 2 Anisa 1072 C A PHE 152 1457 1291 2353 -102 -34 3 0 4 ATÓM 1073 C PHE 152 10.406 19.056 34 .695 1,000 1 3. 9 3 Anisa 1073 C PHE 152 1481 1400 2412 -43 -165 196 ATÓM 1074 0 PHE 152 9679 18.495 35.558 1,000 1 4. 5 0 Anisa 1074 0 PHE 152 1590 1482 2438 -85 25 2 ! 6 ATÓM 1075 CB PHE 152 12.309 17.744 33.728 1,000 1 3. 9 5 Anisa 1075 CB PHE 152 1504 1547 2248 -29 111 4 6 3 ATÓM 1076 CG PHE 152 12.475 16.966 35.011 1,000 1 4. 0 4 Anisa 1076 CG PHE 152 1747 1386 2200 88 -58 2 4 7 ATÓM 1077 CD1 PHE 152 12.032 15.653 35-076 1,000 1 3. 9 0 Anisa 1077 CD1 PHE 152 1906 1306 2069 165 - 3 6 2 8 1 ATÓM 1078 CD2 PHE 152 13.094 17.499 36.127 1,000 1 5. 6 7 Anisa 1078 CD2 PHE 152 1927 1770 2259 -155 -115 i 2 3 3 ATÓM 1079 CE1 PHE 152 12.213 14.949 36.263 1,000 1 4. 0 6 Anisa 1079 CE1 PHE 152 1669 1507 2165 182 -282 ! 3 4 7 ATÓM 1080 CE2 PHE 152 13.323 16.799 37.276 1,000 1 4. 8 3 Anisa 1080 CE2 PHE 152 1724 1671 2240 35 -112 1 . 6 5 ATÓM 1081 CZ PHE 152 12.861 15.522 37.361 1,000 1 4. 86 Anisa 1081 CZ PHE 152 1994 1734 1916 -162 9 9 .1 . 1 3 ATÓM 1082 N LEU 153 10.789 20.324 34.789 1,000 1 5. 2 5 Anisa 1082 N LEU 153 1742 1355 2696 57 110 15 4 ATÓM 1083 C A LEU 153 10.454 21.151 35939 1,000 14. 65 Anisa 1083 CA LEU 153 1783 1429 2354 -66 16 2 0 3 ATÓM 1084 C LEU 153 9.082 21.791 35.877 1,000 14. 4 7 Anisa 1084 C LEU 153 1732 1402 2362 -80 76 1 . 1 ATÓM 1085 0 LEU 153 8.581 22.216 36.953 1,000 15 Dec 82 Anisa 1085 0 LEU 153 1940 1454 2616 -313 312 - 1 5 6 ATÓM 1086 CB LEU 153 11.537 22.224 36.165 1,000 1 6. 53 Anisa 1086 CB LEU 153 1626 1451 3205 -23 269 - 8 3 ATÓM 1087 CG LEU 153 12.914 21.685 36.514 1,000 1 5. 90 Anisa 1087 CG LEU 153 1893 2013 2135 -33 -186 - 3 7 ATÓM 1088 CD1 LEU 153 13.922 22.829 36.614 1,000 1 8. 4 1 Anisa 1088 CD1 LEU 153 1732 2473 2791 -156 80 - 876 ATÓM 1089 CD2 LEU 153 12.863 20.883 37.794 1,000 2 1. 7 6 Anisa 1089 CD2 LEU 153 3083 3182 2005 365 261 19 3 ATÓM 1090 N ASP 154 8.473 21.866 34.708 1,000 14. 4 1 Anisa 1090 N ASP 154 1768 1181 2525 -25 -8 2 ! 9 3 ATÓM 1091 CA ASP 154 7092 22.373 34553 1,000 1 5. 9 0 Anisa 1091 CA ASP 154 1665 1615 2760 -195 28 7 6 9 ATÓM 1092 C ASP 154 6216 21.161 34.814 1,000 1 4. 6 6 Anisa 1092 C ASP 154 1859 1304 2409 -92 143 5 15 ATÓM 1093 0 ASP 154 5.995 20.368 33.889 1,000 1 7. 3 0 Anisa 1093 0 ASP 154 2561 1455 2557 -29 314 2 3 4 ATÓM 1094 CB ASP 154 6923 22.909 33.125 1,000 1 8. 5 9 Anisa 1094 CB ASP 154 1905 2077 3081 124 269 13 17 ATÓM 1095 CG ASP 154 5.461 23.157 32.768 1,000 1 9. 8 7 Anisa 1095 CG ASP 154 2029 2531 2990 226 129 14 3 6 ATÓM 1096 OD1 ASP 154 4. 561 23.253 33.639 1,000 1 9. 6 8 Anisa 1096 OD1 ASP 154 1949 2209 3318 93 221 4 9 6 ATÓM 1097 OD2 ASP 154 5.207 23. 189 31.554 1,000 2 3. 7 3 Anisa 1097 OD2 ASP 154 2512 3475 3029 246 -137 653 ATÓM 1098 N CYS 155 5.831 20.904 36.070 1. 000 1 4. 2 5 Anisa 1098 N CYS 155 1708 1365 2342 -101 -62 5 4 6

SUBSTY SHEET (RULE 26)

WO 99/33994 1'CT / GB9S / 03860

ATÓM 1099 C A CYS 155 5. 41S 19.569 3 6.4 6 N 1 .000 1 3. -1 Ξ Anisa 1099 C A CYS 155 1608 1346 215 8 -191 4--4 5 8 ATÓM 1100 C CYS 155 4,157 19.574 37.302 1. 000 12:49 Anisa 1100 C CYS 155 1644 1331 1772 -200 -148 6 2 ATÓM 1101 0 CYS 155 3. 224 20.303 36.941 1. 000 14:55 Anisa 1101 0 CYS 155 1633 1492 24C2 -122 -111 442 ATÓM 1102 CB CYS 155 6.664 18.872 37098 1,000 14:37 Anisa 1102 CB CYS 155 1907 1366 2186 122 -1 37 2 1 0 ATÓM 1103 SG CYS 155 7.265 19.595 38.641 1,000 14.99 Anisa 1103 SG CYS 155 1561 1821 2315 -74 -98 182 ATÓM 1104 N GLU 156 4.060 18.706 38.316 1,000 12.89 Anisa 1104 N GLU 156 1575 1379 1945 -130 29194 ATÓM nose CA GLU 156 2.788 18.447 39029 1,000 12.98 Anisa 1105 C A GLU 156 1508 1311 2114 -210 2114 0 ATÓM 1106 C GLU 156 2.987 18.676 40.510 1,000 12:34 Anisa 1106 C GLU 156 1414 1198 2078 102 24 2 0 4 ATÓM 1107 0 GLU 156 2.828 17.757 41.289 1. 000 14.89 Anisa 1107 0 GLU 156 1875 1425 2359 -15 -54 442 ATÓM 1108 CB GLU 156 2,278 17.047 38.678 1. 000 14:48 Anisa 1108 CB GLU 156 1968 1323 2213 -279 121 8 7 ATÓM 1109 CG GLU 156 1.855 17038 37.227 1,000 14.86 Anisa 1109 CG GLU 156 1894 1526 2227 -120 95-15 2 ATÓM 1110 CD GLU 156 0.523 17.687 36.932 1,000 17:10 Anisa 1110 CD GLU 156 2091 1976 2431 44 -4 14 4 ATÓM 1111 OE1 GLU 156 -0,204 17.967 37.886 1,000 17.98 Anisa 1111 OE1 GLU 156 1811 2155 2866 -35 10 - 3 4 5 ATÓM 1112 OE2 GLU 156 0214 17.990 35.759 1,000 2 0.99 Anisa 1112 OE2 GLU 156 2854 2419 2704 -386 -516 5 6 2 ATÓM 1113 N PRO 157 3.292 19.893 40.958 1,000 9.12 Anisa 1113 N PRO 157 1314 1347 1934 -48 2 4 9 ATÓM 1114 CA PRO 157 3576 20.121 42391 1,000 13:28 Anisa 1114 CA PRO 157 1425 1696 1924 -68 117 147 ATÓM 1115 C PRO 157 2.330 19.996 43.248 1,000 12.87 Anisa 1115 C PRO 157 1236 1737 1916 -214 -47 124 ATÓM 1116 0 PRO 157 1,192 20.190 42.744 1,000 13.73 Anisa 1116 0 PRO 157 1286 1717 2214 -190 -17 143 ATÓM 1117 CB PRO 157 4061 21.580 42.407 1,000 13.94 Anisa 1117 CB PRO 157 1518 1729 2047 -289 -166 247 ATÓM 1118 CG PRO 157 3363 22.184 41.226 1,000 13.6 Anisa 1118 CG PRO 157 1558 1518 188 7 -32 -158-8 8 ATÓM 1119 CD PRO 157 3.494 21.128 40. 167 1,000 3.12 Anisa 1119 CD PRO 157 1521 1081 1963 -2 -7 12 1 ATÓM 1120 N LEU 158 2.542 19.738 44526 1,000 2.13 Anisa 1120 N LEU 158 1554 1493 1899 -124 148 7 3 ATÓM 1121 CA LEU 158 1,438 19.699 45.496 1,000 12.72 Anisa 1121 CA LEU 158 1465 1552 181 5 -126 -14 3 6 ATÓM 1122 C LEU 158 1927 20.389 46.772 1,000 12.90 Anisa 1122 C LEU 158 1230 1715 1957 -27 -29 -80 ATÓM 1123 0 LEU 158 2.975 19.977 47.289 1,000 6.14 Anisa 1123 0 LEU 158 1374 1666 2304 60 -257 - 2 3 6 ATÓM 1124 CB LEU 158 1,046 18.244 45.315 1,000 13:58 Anisa 1124 CB LEU 158 1673 1590 189 5 -213 57171 ATÓM 1125 CG LEU 158 0044 18.030 46.945 1,000 14.84 Anisa 1125 CG LEU 158 1471 1774 2395 -16 262 242 ATÓM 1126 CD1 LEU 158 -1,333 18.635 46.Ó71 1,000 16.96 Anisa 1126 CD1 LEU 158 1485 2196 276 1 5 -149 - 4 0 1 ATÓM 1127 CD2 LEU 158 -0,142 16.539 47.L61 1,000 14.98 Anisa 1127 CD2 LEU 158 1976 1820 1897 -390 171 7 9 ATÓM 1128 N LEU 159 1.139 21.306 47283 1,000 13:44 Anisa 1128 N LEU 159 1509 1434 2165 4 3 -87-1 1 9 ATÓM 1129 CA LEU 159 1,443 21.963 48.571 1. 000 13:39

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S / 03S60

Anisa 1129 C A LEU 159 1438 1555 2095 -36 -80 -91 ATÓM 1130 C LEU 159 0419 21.494 49.602 1.000 T 4? 4 9 Anisa 1130 C LEU 159 1336 2034 2135 -152 -20S-3 8 ATÓM 1131 0 LEU 159 -0,790 21.596 49.419 I.000 15 0 9 Anisa 1131 0 LEU 159 1414 1999 2319 90 -131 9 ATÓM 1132 CB LEU 159 1.390 23.466 48.394 1.000 15:28 Anisa 1132 CB LEU 159 1720 1447 2638 55 -325 - 1 9 7 ATÓM 1133 CG LEU 159 1,484 24.320 49.669 1.000 17:11 Anisa 1133 CG LEU 159 2146 1689 2665 363 -3 3 2 3 4 3 ATÓM 1134 CD1 LEU 159 2,775 24.114 50.453 1.000 18.70 Anisa 1134 CD1 LEU 159 2276 1759 3070 379 -667 -540 ATÓM 1135 CD2 LEU 159 1,312 25.801 49.291 1.000 2 1.00 Anisa 1135 CD2 LEU 159 2918 1535 3526 439 -692 - 3 8 ATÓM 1136 N ARG 160 0916 21.107 50.774 1.000 14:37 Anisa 1136 N ARG 160 1688 1709 2063 -101 -187 4 7 ATÓM 1137 CA ARG 160 0055 20.747 51.901 1.000 15.61 Anisa 1137 CA ARG 160 1726 1990 2217 -64 90-1 1 8 ATÓM 1138 C ARG 160 0.480 21.501 53.155 1.000 15:40 Anisa 1138 C ARG 160 1557 2158 2135 -34 -46 - 3 8 ATÓM 1139 0 ARG 160 1.639 21.401 53.576 1.000 16:32 Anisa 1139 0 ARG 160 1528 2508 2163 63 41 -10 4 ATÓM 1140 CB ARG 160 0048 19.263 52.227 1.000 16:13 Anisa 1140 CB ARG 160 2134 2084 1912 -127 -30 129 ATÓM 1141 CG ARG 160 -0,594 18.410 51.155 1.000 17:17 Anisa 1141 CG ARG 160 1963 1934 2628 -140 -212 - 6 0 ATÓM 1142 CD ARG 160 -0,672 16.959 51.627 1.000 18:16 Anisa 1142 CD ARG 160 2767 1965 2166 125 -330 - 3 ATÓM 1143 NE ARG 160 -1,382 16.102 50.682 1.000 18:11 Anisa 1143 NE ARG 160 2408 1775 2699 -56 -308 2 0 ATÓM 1144 CZ ARG 160 -1,221 14.789 50.581 1.000 16.76 Anisa 1144 CZ ARG 160 2191 1748 2428 -97 55174 ATÓM 1145 NH1 ARG 160 -0,326 14.192 51.374 1.000 2 0.55 Anisa 1145 NH1 ARG 160 2306 2012 3491 -26 -457 305 ATÓM 1146 NH2 ARG 160 -1,908 14.095 49.689 1.000 19:23 Anisa 1146 NH2 ARG 160 2502 2031 2774 181 -147 - 3 ATÓM 1147 N PHE 161 -0,469 22.257 53.755 1.000 15:36 Anisa 1147 N PHE 161 1604 2120 2111 -37 -63 -128 ATÓM 1148 CA PHE 161 -0,209 22.975 54.999 1.000 16:25 Anisa 1148 CA PHE 161 2173 1774 2227 -71 -187-8 9 ATÓM 1149 C PHE 161 -1,030 22.236 56.069 1.000 16.98 Anisa 1149 C PHE 161 1980 2432 2041 -217 -161-16 16 ATÓM 1150 0 PHE 161 -2,248 22.113 55.948 1.000 2 0.38 Anisa 1150 0 PHE 161 1981 3291 2473 -190 -191-7 2 ATÓM 1151 CB PHE 161 -0,683 24.431 54.862 1.000 19.76 Anisa 1151 CB PHE 161 2065 1903 3540 167 355 - 1 9 7 ATÓM 1152 CG PHE 161 -0,379 25.259 56.109 1.000 2 3.61 Anisa 1152 CG PHE 161 3026 1905 4041 836 -59-5 5 9 1 ATÓM 1153 CD1 PHE 161 -1,194 25.304 57.228 1.000 8.25 Anisa 1153 CD1 PHE 161 3992 2474 4268 1077 369 -1253 ATÓM 1154 CD2 PHE 161 0807 25.978 56.141 1.000 6.62 Anisa 1154 CD2 PHE 161 4015 2483 3616 -130 -927 - 1 0 7 ATÓM 1155 CE1 PHE 161 -0,850 25.992 58.383 1.000 5.29 Anisa 1155 CE1 PHE 161 6873 2097 4437 1538 -135-1 3 9 9 ATÓM 1156 CE2 PHE 161 1.153 26.723 57.258 1.000 3 3.63 Anisa 1156 CE2 PHE 161 4643 3240 4894 1263 -2086 - 1 2 6 8 ATÓM 1157 CZ PHE 161 0.320 26.726 58.363 1.000 6.44 Anisa 1157 CZ PHE 161 6071 4282 3493 1455 -2478 - 1 0 4 4 ATÓM 1158 N ARG 162 -0,358 21.767 57.130 1.000 17:59 Anisa 1158 N ARG 162 2095 2487 2103 -118 -135-6 9 ATÓM 1159 CA ARG 162 -1,072 21.078 58.199 1.000 18:27 Anisa 1159 CA ARG 162 2769 2414 1759 6 17 8 -373

SUBSTTrUTE SHEET (RULE 26)

WO 99/33994 lCT / GB9S / 03860

ATÓM 1160 C ARG 162 -0,830 21.758 59.553 1,000 2 0.16 Anisa 1160 C ARG 162 2110 334 1 2210 - 3 ó 4Ί- '9 6 0 ATÓM 1161 ABOUT ARG 162 0217 22.160 59.893 1. 000 19.61 Anisa 1161 ABOUT ARG 162 2257 2993 2201 - 194 -73- 3 5 9 ATÓM 1162 CB ARG 162 -0,580 19.640 58. 356 1,000 2 0.81 Anisa 1162 CB ARG 162 2958 2275 2675 -129 ó - 1 6 9 ATÓM 1163 CG ARG 162 -0,843 18724 57.166 1,000 19.90 Anisa 1163 CG ARG 162 3044 2073 2 44 3 -112 254 - 3 7 ATÓM 1164 CD ARG 162 -0,182 17.383 57.393 1. 000 2 8.02 Anisa 1164 CD ARG 162 5599 2038 3010 381 -14 114 ATÓM 1165 NE ARG 162 -0,369 16.420 56. 326 1,000 7.74 Anisa 1165 NE ARG 162 4151 2294 4097 555 -687 - 4 ATÓM 1166 CZ ARG 162 -1,278 15.445 56.370 1,000 3 1.11 Anisa 1166 CZ ARG 162 2560 3729 5531 470 -350-1 1 1 5 2 ATÓM 1167 NH1 ARG 162 -2,092 15.324 57 403 1,000 4 2.97 Anisa 1167 NH1 ARG 162 3475 5906 6946 -579 1019-2 4 9 2 ATÓM 1168 NH2 ARG 162 -1,329 14.603 55 353 1,000 9.64 Anisa 1168 NH2 ARG 162 3066 2738 5458 120 -143 - 7 0 7 ATÓM 1169 N TYR 163 -1,956 21.780 60.311 1,000 19:52 Anisa 1169 N TYR 163 2394 2901 212 0 147 263-7 6 3 ATÓM 1170 CA TYR 163 -1,943 22.102 61732 1,000 2 2.74 Anisa 1170 CA TYR 163 3312 3107 2219 369 302-8 7 8 ATÓM 1171 C TYR 163 -2,037 20.800 62536 1,000 4.20 Anisa 1171 C TYR 163 2802 3901 2492 -222 253-1 8 9 ATÓM 1172 ABOUT TYR 163 -2,992 20.049 62.274 1,000 2 8.02 Anisa 1172 ABOUT TYR 163 2305 4409 3934 -202 -126 399 ATÓM 1173 CB TYR 163 -3,198 22.912 62114 1,000 8.98 Anisa 1173 CB TYR 163 3861 3231 3920 267 1196-178 3 ATÓM 1174 CG TYR 163 -3,342 22.997 63623 1,000 5.58 Anisa 1174 CG TYR 163 2572 3382 3767 543 749 -1204 ATÓM 1175 CD1 TYR 163 -2,458 23.826 64319 1,000 37.32 Anisa 1175 CD1 TYR 163 3654 6112 4413 -759 883 - 2 3 7 4 ATÓM 1176 CD2 TYR 163 -4,315 22.333 64345 1,000 9.13 Anisa 1176 CD2 TYR 163 2622 3994 4452 749 1084 - 7 7 9 ATÓM 1177 CE1 TYR 163 -2,546 23.966 65702 1,000 8.28 Anisa 1177 CE1 TYR 163 2905 7138 4503 -454 986 - 2 7 4 0 ATÓM 1178 CE2 TYR 163 -4,396 22.431 65726 1,000 37.36 Anisa 1178 CE2 TYR 163 3220 6336 4640 -273 1997 - 1 6 1 9 ATÓM 1179 CZ TYR 163 -3,500 23.250 66393 1,000 4 9.85 Anisa 1179 CZ TYR 163 5272 8795 4872 -1810 1594 - 2 2 2 3 ATÓM 1180 OH TYR 163 -3,595 23.365 67768 1,000 4 4.81 Anisa 1180 OH TYR 163 5246 7368 4413 -222 270-4 9 6 ATÓM 1181 N PHE 164 -1,098 20.651 63.448 1,000 24.84 Anisa 1181 N PHE 164 2905 3368 3164 -89 - 125 - 3 6 1 ATÓM 1182 CA PHE 164 -1,045 19.532 64.370 1,000 8.14 Anisa 1182 CA PHE 164 3538 3957 3195 223 -163-3 3 0 ATÓM 1183 C PHE 164 -1,360 20.003 65787 1,000 6.67 Anisa 1183 C PHE 164 2964 3937 3234 -473 -194 - 2 6 7 ATÓM 1184 ABOUT PHE 164 -0,540 20.730 66342 1,000 3 1.26 Anisa 1184 ABOUT PHE 164 3119 4888 3869 -959 -260 - 5 0 9 ATÓM 1185 CB PHE 164 0347 18.881 64.396 1,000 7.86 Anisa 1185 CB PHE 164 3423 3725 3436 77 -199 - 3 2 ATÓM 1186 CG PHE 164 0744 18.301 63.052 1,000 6.77 Anisa 1186 CG PHE 164 2914 3474 3785 -598 74 - 2 6 5 ATÓM 1187 CD1 PHE 164 1,435 19.093 62143 1,000 6.16 Anisa 1187 CD1 PHE 164 2827 3836 3278 135 -615 711 ATÓM 1188 CD2 PHE 164 0414 16.996 62717 1,000 3 1.24 Anisa 1188 CD2 PHE 164 4365 2808 4698 349 -298-9 6 ATÓM 1189 CE1 PHE 164 1,787 18.609 60894 1,000 3 0.09 Anisa 1189 CE1 PHE 164 3609 5052 2771 - 148 -1030 641 ATÓM 1190 CE2 PHE 164 0.786 16.501 61475 1,000 3 e. 2 5

SUBSTTTUTE SHEET (RULE 26)

WO 99'33994 lCT / GB98'03860

Anisa 1190 CE2 PF E 1 ó 4 6659 4 077 3797 -740 -.13 6 3 - 5 i? ATÓM 1191 CZ PHE 164 1494 17.298 60588 1,000 3 2 ’. 7 4 Anisa 1191 CZ PHE 164 3189 5078 4 172 712 - 94 4 - 3 8 5 ATÓM 1192 N PRO 165 -2,469 19.609 66379 í. 000 3 0.62 Anisa 1192 N PRO 165 3876 4 009 3751 -1371 344 - 5 0 7 ATÓM 1193 C A PRO 165 -2,670 19.813 67809 1,000 3 3.09 Anisa 1193 CA PRO 165 3299 5764 3510 -190 81 2 3 6 ATÓM 1194 C PRO 165 -1,459 19.408 68.638 1,000 6.32 Anisa 1194 C PRO 165 3538 5745 4518 664 -191-234 ATÓM 1195 0 PRO 165 -0,776 18.428 68371 1,000 3 2.94 Anisa 1195 0 PRO 165 4268 4761 3487 220 501 387 ATÓM 1196 CB PRO 165 -3,882 18.929 68123 1,000 8.44 Anisa 1196 CB PRO 165 3807 6924 3873 -765 271 827 ATÓM 1197 CG PRO 165 -4,635 18.842 66.845 1,000 3 5.82 Anisa 1197 CG PRO 165 2595 7020 3995 5 678 - 8 2 8 ATÓM 1198 CD PRO 165 -3,690 19.130 65710 1,000 3 3.90 Anisa 1198 CD PRO 165 3192 5919 3770 -1149 194 169 ATÓM 1199 N LEU 178 7727 7453 68180 1,000 64.52 Anisa 1199 N LEU 178 12297 5376 6843 278 -218 3 7 2 2 ATÓM 1200 C A LEU 178 7629 8.260 66973 1,000 4 3.31 Anisa 1200 CA LEU 178 10557 2730 3168 -984 -2821 - 1 3 ATÓM 1201 C LEU 178 6159 8.539 66662 1,000 7.36 Anisa 1201 C LEU 178 9239 3530 5225 -2,598 -1185 1 2 0 4 ATÓM 1202 0 LEU 178 5314 7.659 66796 1,000 6.53 Anisa 1202 0 LEU 178 11777 5626 4076 -4,835 1265 - 6 0 1 ATÓM 1203 CB LEU 178 8.222 7582 65746 1,000 55.55 Anisa 1203 CB LEU 178 11470 3734 5902 -1314 -1198 - 1 8 2 2 ATÓM 1204 CG LEU 178 9662 7092 65774 1,000 62.34 Anisa 1204 CG LEU 178 10812 5116 7760 -1971 195 - 4 4 3 ATÓM 1205 CD1 LEU 178 9.916 6.185 64579 1,000 54.23 Anisa 1205 CD1 LEU 178 9626 4989 5988 1878 -3799 511 ATÓM 1206 CD2 LEU 178 10.633 8264 65773 1,000 6.44 Anisa 1206 CD2 LEU 178 11265 3454 10526 -1170 4090 - 5 1 7 ATÓM 1207 N ARG 179 5.879 9751 66192 1,000 52.90 Anisa 1207 N ARG 179 7853 3826 8421 102 1231 1 0 3 1 ATÓM 1208 CA ARG 179 4,495 10.033 65807 1,000 51.26 Anisa 1208 CA ARG 179 7235 4820 7421 -229 1890 - 3 8 ATÓM 1209 C ARG 179 4242 9.563 64383 1,000 5.25 Anisa 1209 C ARG 179 7178 6083 7731 -946 2260 - 1 2 3 4 ATÓM 1210 0 ARG 179 3.120 9,211 64.021 1,000 8.51 Anisa 1210 0 ARG 179 7036 7628 7565 -1820 3675 -2851 ATÓM 1211 CB ARG 179 4,180 11.512 66040 1,000 4 1.49 Anisa 1211 CB ARG 179 6600 4448 4716 -155 1915 113 7 ATÓM 1212 CG ARG 179 3,293 11.700 67277 1,000 43.15 Anisa 1212 CG ARG 179 6120 5908 4367 90 1338 530 ATÓM 1213 CD ARG 179 1.888 12.059 66833 1,000 47.63 Anisa 1213 CD ARG 179 6180 7453 4463 195 860 - 5 4 1 ATÓM 1214 NE ARG 179 1,459 13.367 67269 1,000 52.00 Anisa 1214 NE ARG 179 7384 7834 4539 1669 -1167 - 5 3 8 ATÓM 1215 CZ ARG 179 1,322 14.470 66556 1,000 4.81 Anisa 1215 CZ ARG 179 10838 8000 5788 1457 -1107 6 3 ATÓM 1216 NH1 ARG 179 1,637 14.518 65268 1,000 9.74 Anisa 1216 NH1 ARG 179 9535 8090 5074 3628 -2691 445 ATÓM 1217 NH2 ARG 179 0.907 15.606 67117 1,000 65.83 Anisa 1217 NH2 ARG 179 10451 9083 5478 4171 -777 1 2 0 0 ATÓM 1218 N MET 180 5.304 9.501 63589 1,000 4 3.96 Anisa 1218 N MET 180 5383 3769 7550 705 851 - 1 2 4 5 ATÓM 1219 CA MET 180 5264 9035 62.210 1,000 4 0.44 Anisa 1219 CA MET 180 2356 5467 7543 -398 575 - 1 4 8 2 ATÓM 1220 C MET 180 6552 8.258 61.920 1,000 4 3.91 Anisa 1220 C MET 180 2731 6220 7733 18 32 0 - 2 3 2 5

SUBSTTTirrE SHEET (RULE 26)

WO 99/3394

PCT / GB9SOJS60

ATÓM 12 21 ABOUT MET 180 7629 8. 679 62327 1,000 3 9.46 Anisa 1221 ABOUT MET 180 2377 5064 7554 -395 - 9 1 2 ATÓM 1222 CB MET 180 5.129 10.189 61219 1,000 4 9.84 Anisa 1222 CB MET 180 2749 7966 822 3 -4 52 -1115 7 2 ATÓM 1223 CG MET 180 5 .339 9.818 59757 1,000 62.58 Anisa 1223 CG MET 180 7280 8911 7587 -2,331 -3353 -505 ATÓM 1224 SD MET 180 4,622 11.015 58608 1,000 7 4.24 Anisa 1224 SD MET 180 7480 13510 7216 4918 -2c2 9 9 5 ATÓM 1225 CE MET 180 4. 501 10.037 57.110 1,000 9.59 Anisa 1225 CE MET 180 6119 20000 4120 -1978 1874-9 1 2 ATÓM 1226 N ALA 181 6376 7.112 61275 1,000 7.44 Anisa 1226 N ALA 181 3523 5646 50 55 -271 881 - 1 1 2 ATÓM 1227 C A ALA 181 7407 6.140 60.986 1,000 3 7.40 Anisa 1227 C A ALA 181 3980 3980 62'5 0 -625 2048 461 ATÓM 1223 C ALA 181 8287 6.591 59837 1,000 3 1.49 Anisa 1228 C ALA 181 2975 3842 514 9 -32 920 956 ATÓM 1229 ABOUT ALA 181 7.834 7393 58.997 1,000 3 0.77 Anisa 1229 ABOUT ALA 181 2903 4021 476 5 197 -98 164 ATÓM 1230 CB ALA 181 6.727 4817 60.620 1,000 4 2.66 Anisa 1230 CB ALA 181 4105 4284 782 0 -1023 1629 557 ATÓM 1231 N PRO 182 9.541 6137 59. 840 1,000 4.52 Anisa 1231 N PRO 182 2782 4237 22 9 6 -240 -76 320 ATÓM 1232 C A PRO 182 10.442 6.667 58. 820 1,000 2 0.55 Anisa 1232 C A PRO 182 2612 2870 2326 -335 -117-6 6 ATÓM 1233 C PRO 182 9.958 6402 57.408 1,000 19:31 Anisa 1233 C PRO 182 2609 2491 223 6 -391 48-86 ATÓM 1234 ABOUT PRO 182 9.448 5326 57.080 1,000 2 1.68 Anisa 1234 ABOUT PRO 182 2991 2486 2759 -440 -340 - 5 ATÓM 1235 CB PRO 182 11.768 5939 59047 1,000 2 4.98 Anisa 1235 CB PRO 182 2589 3860 3042 -170 -286 153 ATÓM 1236 CG PRO 182 11.681 5.351 60393 1,000 8.42 Anisa 1236 CG PRO 182 3352 3582 38 63 656 320 1 0 3 8 ATÓM 1237 CD PRO 182 10.215 5.210 60747 1,000 2.21 Anisa 1237 CD PRO 182 3333 4905 4000 -826 -391 1 7 8 5 ATÓM 1238 N HIS 183 10.111 7,414 56.561 1,000 19:27 Anisa 1238 N HIS 183 2131 2658 2 53 3 -274 -204 176 ATÓM 1239 CA HIS 183 9.757 7.306 55.144 1,000 1.18 Anisa 1239 CA HIS 183 1882 2311 2 65 2 -341 -455 346 ATÓM 1240 C HIS 183 10.749 8124 54337 1,000 15.74 Anisa 1240 C HIS 183 1964 1560 2456 -75 -352 128 ATÓM 1241 ABOUT HIS 183 11.355 9.061 54.868 1,000 18:14 Anisa 1241 ABOUT HIS 183 2297 2093 2504 -509 -127-1 ATÓM 1242 CB HIS 183 8.338 7781 54835 1,000 18.66 Anisa 1242 CB HIS 183 1970 2173 2 94 5 -136 -243 371 ATÓM 1243 CG HIS 183 8.089 9.120 55447 1,000 6.67 Anisa 1243 CG HIS 183 3100 2751 4281 262 222 - 3 0 7 ATÓM 1244 ND1 HIS 183 7.884 9.362 56.800 1,000 5.36 Anisa 1244 ND1 HIS 183 4432 4078 4 92 6 -1190 1467 - 1 4 5 4 ATÓM 1245 CD2 HIS 183 8.051 10.311 54821 1,000 3 3.00 Anisa 1245 CD2 HIS 183 4117 2522 5898 1687 -677-1 7 ATÓM 1246 CE1 HIS 183 7739 10.658 56.980 1,000 3 5.91 Anisa 1246 CE1 HIS 183 2611 4468 6 5 6 5 -472 -625 - 2 5 1 6 ATÓM 1247 NE2 HIS 183 7829 11.251 55798 1,000 4 0.55 Anisa 1247 NE2 HIS 183 4375 3417 7614 1821 -1013 -1590 ATÓM 1248 N TYR 184 10.890 7.778 53.061 1,000 15.68 Anisa 1248 N TYR 184 1973 1551 2434 -124 -470 107 ATÓM 1249 CA TYR 184 11,605 8.685 52.152 1,000 14.81 Anisa 1249 CA TYR 184 1798 1392 243 8 147 -312 145 ATÓM 1250 C TYR 184 10.572 9,239 51.169 1,000 14:53 Anisa 1250 C TYR 184 1656 1449 2 416 -70 -399 9 8 ATÓM 1251 0 TYR 184 9.468 8.728 51 045 1,000 15 8 3

SUBSTTrUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

Anisa 1251 ABOUT TYR ATÓM 1252 CB TYR Anisa 1252 CB TYR ATÓM 1253 CG TYR Anisa 1253 CG TYR ATÓM 1254 CD1 TYR Anisa 1254 CD1 TYR ATÓM 1255 CD2 TYR Anisa 1255 CD2 TYR ATÓM 1256 CE1 TYR Anisa 1256 CE1 TYR ATÓM 1257 CE2 TYR Anisa 1257 CE2 TYR ATÓM 1258 CZ TYR Anisa 1258 CZ TYR ATÓM 1259 OH TYR Anisa 1259 OH TYR ATÓM 1260 N ASP Anisa 1260 N ASP ATÓM 1261 CA ASP Anisa 1261 CA ASP ATÓM 1262 C ASP Anisa 1262 C ASP ATÓM 1263 ABOUT ASP Anisa 1263 ABOUT ASP ATÓM 1264 CB ASP Anisa 1264 CB ASP ATÓM 1265 CG ASP Anisa 1265 CG ASP ATÓM 1266 OD1 ASP Anisa 1266 OD1 ASP ATÓM 1267 OD2 ASP Anisa 1267 OD2 ASP ATÓM 1268 N LEU Anisa 1268 N LEU ATÓM 1269 CA LEU Anisa 1269 CA LEU ATÓM 1270 C LEU Anisa 1270 C LEU ATÓM 1271 ABOUT LEU Anisa 1271 ABOUT LEU ATÓM 1272 CB LEU Anisa 1272 CB LEU ATÓM 1273 CG LEU Anisa 1273 CG LEU ATÓM 1274 CD1 LEU Anisa 1274 CD1 LEU ATÓM 1275 CD2 LEU Anisa 1275 CD2 LEU ATÓM 1276 N SER Anisa 1276 N SER ATÓM 1277 CA SER Anisa 1277 CA SER ATÓM 1278 C SER Anisa 1278 C SER ATÓM 1279 ABOUT SER Anisa 1279 ABOUT SER ATÓM 1280 CB SER Anisa 1280 CB SER ATÓM 1281 OG SER Anisa 1281 OG SER

184 1717 1383 2916 184 12.699 8.004 51.360 184 1686 1323 2943 184 12.383 6.785 50562 184 1743 1313 2586 184 12.200 5.540 51.185 184 1549 1315 3021 184 12.329 6.836 49.165 184 1724 1763 2552 184 11,962 4396 50.442 184 1695 1244 2992 184 12.130 5661 48.447 184 2340 1776 2540 184 11.915 4449 49.083 184 1695 1736 3014 184 11.682 3,325 48.310 184 2020 1775 3352 185 10.924 10.330 50.502 185 1518 1599 2338 185 10.026 11.005 49.574 185 1875 1322 2078 185 10.240 10.490 48.152 185 1182 1385 2211 185 11.357 10.135 47.824 185 1177 1637 2559 185 10.294 12.521 49.580 185 1879 1293 2517 185 9.702 13.155 50.830 185 2680 1659 2351 185 9.507 12.466 51856 185 3553 3133 2314 185 9.174 14.257 50742 185 4063 1730 3449 186 9,141 10.465 47.382 186 1271 1378 2126 186 9169 10.091 45.986 186 1533 1225 2150 186 9.134 11.292 45.052 186 1730 1307 2330 186 8971 11.173 43.849 186 3721 1643 2280 186 8.040 9.106 45.609 186 1509 1310 2393 186 8.020 7.811 46.438 186 1549 1141 3361 186 6929 6.908 45.866 186 1686 1845 3825 186 9.369 7.115 46.341 186 1689 1742 3528 187 9.286 12.494 45.618 187 1326 1234 2608 187 9388 13.734 44.826 187 1489 1197 2338 187 10.736 13.853 44.134 187 1482 1186 2192 187 11.683 13,076 44.356 187 1532 1257 2720 187 9.201 14.915 45.811 187 1463 1282 2147 187 10.296 14.873 46.716 187 1589 1420 2015

-103 -443 150 1,000 1-S- ȣ 5 69 -3 < 55 - 1 6 8 1,000 14.85 109 -568 4 3 1,000 15:49 -29 -575 190 1,000 15.89 55 -27-64 1,000 15.61 229 -137 1 1 3 1,000 17:52 4 83 -90 1,000 16.96 -156 -480 3 4 1,000 18.81 260 -277 - 3 1,000 14:36 87 -225 276 1,000 13.88 141 -364 - 4 1,000 12:57 -160 -77 -13 0 1,000 14:14 -135 146 140 1,000 14.97 121 -186-15 15 1,000 17.61 232 -13 -17 2 1,000 2 3.69 443 -302 521 1,000 24.32 644 1140 - 1 7 1,000 12:57 -117 -117-1 1 7 1,000 12.92 -331 -84 -17 5 1,000 14:12 -93 -166 5 5 1,000 0.12 -423 99 9 2 1,000 13.72 -270 -375-6 1,000 15.92 -145 -307 168 1,000 19:36 -700 -209 396 1,000 18:32 200 -432 179 1,000 13.60 -26 -95 137 1,000 13:22 -54 -68 2 9 1,000 12.79 -17 -114-9 0 1,000 14:50 77 -224 - 1 1 3 1,000 12.87 164 -159 9 8 1,000 13:22 -34 -143 224

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S'0386 ()

ATÓM 12S2 N MET 188 10.898 Anisa 12S2 N MET 188 1552 ATÓM 1283 C A MET 188 12.215 Anisa 1283 CA MET 188 1508 ATÓM 1284 C MET 188 12.853 Anisa 1284 C MET 188 1563 ATÓM 1285 0 MET 188 13 .896 Anisa 1285 0 MET 188 1408 ATÓM 1286 CB MET 188 12.038 Anisa 1286 CB MET 188 1565 ATÓM 1287 CG MET 188 13.296 Anisa 1287 CG MET 188 1697 ATÓM 1288 SD MET 188 14.600 Anisa 1288 SD MET 188 1565 ATÓM 1289 CE MET 188 16.005 Anisa 1289 CE MET 188 1852 ATÓM 1290 N VAL 189 12.244 Anisa 1290 N VAL 189 1586 ATÓM 1291 CA VAL 189 12.565 Anisa 1291 CA VAL 189 1412 ATÓM 1292 C VAL 189 11.285 Anisa 1292 C VAL 189 1328 ATÓM 1293 0 VAL 189 10.227 Anisa 1293 0 VAL 189 1446 ATÓM 1294 CB VAL 189 13.440 Anisa 1294 CB VAL 189 1150 ATÓM 1295 CG1 VAL 189 14.778 Anisa 1295 CG1 VAL 189 1376 ATÓM 1296 CG2 VAL 189 12.730 Anisa 1296 CG2 VAL 189 1763 ATÓM 1297 N THR 190 11.425 Anisa 1297 N THR 190 1445 ATÓM 1298 CA THR 190 10.353 Anisa 1298 CA THR 190 1292 ATÓM 1299 C THR 190 10.879 Anisa 1299 C THR 190 1178 ATÓM 1300 0 THR 190 11.959 Anisa 1300 0 THR 190 1424 ATÓM 1301 CB THR 190 9.913 Anisa 1301 CB THR 190 1509 ATÓM 1302 OG1 THR 190 9.481 Anisa 1302 OG1 THR 190 1693 ATÓM 1303 CG2 THR 190 8.778 Anisa 1303 CG2 THR 190 1696 ATÓM 1304 N LEU 191 10.148 Anisa 1304 N LEU 191 1329 ATÓM 1305 CA LEU 191 10.511 Anisa 1305 CA LEU 191 1543 ATÓM 1306 C LEU 191 9.603 Anisa 1306 C LEU 191 1543 ATÓM 1307 0 LEU 191 8.370 Anisa 1307 0 LEU 191 1517 ATÓM 1308 CB LEU 191 10.398 Anisa 1308 CB LEU 191 1717 ATÓM 1309 CG LEU 191 11.705 Anisa 1309 CG LEU 191 1747 ATÓM 1310 CD1 LEU 191 12.069 Anisa 1310 CD1 LEU 191 2034 ATÓM 1311 CD2 LEU 191 11.570 Anisa 1311 CD2 LEU 191 2297 ATÓM 1312 N ILE 192 10.199

1 4. S 4 4 43.292 1 000 13:44 1334 222 1 - ô 4 --3A, - 2 6 15.380 42.87S i. 000 12:11 12Ó1 1833 29 -60-6 6 1 16.022 44.104 1. 000 12.78 1156 2136 16 7 -311 - 4 2 15.550 44 .600 1. 000 13:40 1390 2294 116 -264 - 2 6 16.300 41.667 1,000 13.66 1501 2123 44 -161 2 0 7 17.095 41.315 1. 000 5.14 1595 2046 66 15.971 40.752 1,000 14.96 1591 2529 109 -81 1 1 0 17.102 40.686 1,000 17.74 2032 2855 -242 505 1 2 1 17.112 44. 616 1. 000 12.62 1203 2007 103 -147 - 13 4 17.671 45. 918 1,000 12.60 1438 1937 -228 -11 - 4 4 17.968 46. 579 1,000 11.71 1294 182 5 -170 -171 - 4 9 18.099 46.050 1,000 12:56 1291 2 03 5 21 -320 - 4! 9 18.955 45.856 1,000 12.95 1517 2252 -174 -205 9 4 18.637 45.167 1,000 15:54 2094 2437 -140 161 9 1 20.056 45.082 1,000 15:00 1391 2547 -130 -483 8 1 18.067 47.984 1,000 12:18 1422 1760 -109 -130 1 0 18.454 48.897 1,000 11.98 1356 19 03 -57 -221 - 15 1 19.630 49.710 1,000 12:47 1436 212 4 -32 -297 - 2 3 2 19.523 50.320 1,000 6.15 1767 2531 46 -571 4 4 6 17.297 49808 1,000 13:16 1605 1886 -168 81 - 1 2 1 16.201 48.993 1,000 14:47 1469 23 34 -100 -25 - 19 4 17.723 50.734 1,000 14.79 1510 2415 73,258 - 8 9 20.724 49.732 1,000 12.97 1449 2149 23 - 21 - 2 8 6 21.908 50.526 1,000 13.75 1442 2238 -206 - 3 0 1 21.964 51763 1,000 14:47 1689 22 65 82 -179 - 4 1 2 21.868 51.645 1,000 16:58 2486 22 97 219 -176 - 7 2 5 23.212 49722 1,000 15:37 1444 2680 58 -106-1 8 9 23.578 48.973 1,000 16:10 1688 2 68 0 -128 -113 - 1 3 5 22.565 47906 1,000 16.67 2093 2209 -23 -64 1 9 24.959 48.250 1,000 18:53 1906 2 83 7 -345 -4 37 1 4 8 22.148 52.946 1,000 15:36

SUBSTTTUTE SHEET (RULE 26)

WO 99'33994

PCT / GB98 / 03860

Anisa 1312 N ILE 192 1479 2152 2204 -4 7 -165 -16-i ATÓM 1313 CA ILE 192 9417 22.162 54194 1,000 FS »3 Anisa 1313 C Ä ILE 192 1456 2043 2251 -304 -173 - 2 7 0 ATÓM 1314 C ILE 192 9,692 23.423 55.010 I '. 000 15:58 Anisa 1314 C ILE 192 1696 1973 2251 -199 - 254 - 2 2 6 ATÓM 1315 ABOUT ILE 192 10.836 23691 55381 1,000 17:20 Anisa 1315 ABOUT ILE 192 1856 2449 2229 -307 -341-5 5 7 4 ATÓM 1316 CB ILE 192 9.722 20.920 55.040 1,000 3.17 Anisa 1316 CB ILE 192 2246 1958 2266 -52 325 - 3 0 4 ATÓM 1317 CG1 ILE 192 9.454 19.596 54317 1,000 19.80 Anisa 1317 CG1 ILE 192 3040 2010 2473 -71 128 - 3 7 2 ATÓM 1318 CG2 ILE 192 8.995 20.967 56.403 1,000 18:14 Anisa 1318 CG2 ILE 192 2278 2354 2262 229 2 90 - 2 6 8 ATÓM 1319 CDI ILE 192 9.420 18.387 55235 1,000 3 1.57 Anisa 1319 CDI ILE 192 4658 2114 5222 -398 -1094 765 ATÓM 1320 N GLN 193 8.625 24.172 55.249 1,000 4.17 Anisa 1320 N GLN 193 2042 2185 2248 112 -388 - 3 0 0 ATÓM 1321 CA GLN 193 8.680 25.291 56.201 1,000 17.70 Anisa 1321 C A GLN 193 1737 2167 2824 -204 -186 - 5 6 9 ATÓM 1322 C GLN 193 7.898 24.869 57443 1,000 19.67 Anisa 1322 C GLN 193 1882 2624 2969 -232 211-8 4 0 ATÓM 1323 0 GLN 193 7082 23.942 57426 1,000 2 6.60 Anisa 1323 0 GLN 193 2066 3843 4197 -965 -110 6 2 ATÓM 1324 CB GLN 193 8.129 26.598 55.643 1,000 2 3.74 Anisa 1324 CB GLN 193 3070 2388 3561 500 -98-514 ATÓM 1325 CG GLN 193 8913 27.304 54559 1,000 8.26 Anisa 1325 CG GLN 193 4664 2384 3689 656 209 0 ATÓM 1326 CD GLN 193 8.338 28.665 54.156 1,000 2 6.30 Anisa 1326 CD GLN 193 2868 2943 4181 791 3 111 ATÓM 1327 OE1 GLN 193 7193 28.695 53.688 1,000 4 5.31 Anisa 1327 OE1 GLN 193 2826 7147 7241 -51 -616 3 16 3 ATÓM 1328 NE2 GLN 193 9.080 29.748 54.345 1,000 3 0.44 Anisa 1328 NE2 GLN 193 3609 2588 5368 418 1259 692 ATÓM 1329 N GLN 194 8241 25.259 58.645 1,000 2 2.04 Anisa 1329 N GLN 194 2926 2758 2690 303 -368-8 3 ATÓM 1330 CA GLN 194 7569 24.793 59.847 1,000 2 2.68 Anisa 1330 CA GLN 194 3144 2617 2855 81 -230 - 1 5 0 ATÓM 1331 C GLN 194 7.275 26.054 60663 1,000 22:19 Anisa 1331 C GLN 194 2809 2768 2856 117 -396 - 3 0 0 ATÓM 1332 0 GLN 194 7889 27.100 60.418 1,000 5.26 Anisa 1332 0 GLN 194 4041 2877 2679 -313 -21 - 41 1 ATÓM 1333 CB GLN 194 8467 23.943 60739 1,000 9.21 Anisa 1333 CB GLN 194 4493 2707 3899 477 -50 939 ATÓM 1334 CG GLN 194 9.105 22.735 60.083 1,000 2 8.80 Anisa 1334 CG GLN 194 3108 3530 4305 576 -121 4 9 5 ATÓM 1335 CD GLN 194 10.296 22.332 60962 1,000 3 1.97 Anisa 1335 CD GLN 194 2961 5384 3800 824 358 1 0 7 5 ATÓM 1336 OE1 GLN 194 11.421 22.325 60474 1,000 7.28 Anisa 1336 OE1 GLN 194 2781 4189 3397 118 132 - 2 4 9 ATÓM 1337 NE2 GLN 194 9.998 22.100 62232 1,000 2 9.82 Anisa 1337 NE2 GLN 194 3540 3958 3832 989 645 800 ATÓM 1338 N THR 195 6419 25.891 61658 1,000 2 3.30 Anisa 1338 N THR 195 2407 3058 3387 -211 -235-7 2 0 ATÓM 1339 CA THR 195 6.476 26.833 62768 1,000 7.14 Anisa 1339 C A THR 195 3459 3544 3308 25 -50-890 ATÓM 1340 C THR 195 6.933 25.997 63958 1,000 6.11 Anisa 1340 C THR 195 3825 2829 3268 558 19 - 1 2 3 4 ATÓM 1341 0 THR 195 6.639 24.815 63994 1,000 2 8.17 Anisa 1341 0 THR 195 2973 2916 4815 481 171 -1030 ATÓM 1342 CB THR 195 5.149 27.534 63069 1,000 2 5.87 Anisa 1342 CB THR 195 3428 2849 3 551 -16 -592 - 1

SUBSTnUTE SHEET

WO 99/33994

PCT / GB9S / 03860

ATÓM 1343 OG1 THR 195 4.111 26.550 63.196 1,000 25.45 Anisa 1343 OG1 THR 195 3427 3101 314 1 - 9 - 1Ku, - 7 5 0 Atom. 1344 CG2 THR 195 4. 788 28.396 61847 1,000 3 1.31 Anisa 1344 CG2 THR 195 4965 2552 4 380 274 - 70 - 4 0 9 ATÓM 1345 N PRO 196 7. 604 26.587 64923 1,000 3 0.84 Anisa 1345 N PRO 196 5225 3191 3300 785 -517-1 5 5 2 ATÓM 1346 C A PRO 196 8. 101 25.823 66065 1,000 2 8.50 Anisa 1346 C A PRO 196 3113 3700 4016 -279 - 4 4 i - 6 4 6 ATÓM 1347 C PRO 196 7 .018 25.534 67 .096 1,000 8.97 Anisa 1347 C PRO 196 3581 3326 4 102 42 114 - 1 3 8 1 ATÓM 1348 0 PRO 196 6.002 26.229 67192 1. 000 3 2.32 Anisa 1348 0 PRO 196 4146 4649 3485 901 -180 - 1 6 7 8 ATÓM 1349 CB PRO 196 9.094 26816 6 6.694 1,000 9.72 Anisa 1349 CB PRO 196 3888 3292 4111 -285 -353 - 1 0 7 1 ATÓM 1350 CG PRO 196 8.533 28174 6 (i. 3 6 4 1,000 3 4.87 Anisa 1350 CG PRO 196 6285 3575 3 3 90 421 -1326 - 1 2 3 3 ATÓM 1351 CD PRO 196 7897 28.035 65012 1,000 3.20 Anisa 1351 CD PRO 196 6407 3606 2 600 -598 -494 - 1 0 3 0 ATÓM 1352 N CYS 197 7289 24.533 67919 1,000 6.96 Anisa 1352 N CYS 197 2739 4038 34 65 -113 84 - 1 2 2 7 ATÓM 1353 CA CYS 197 6519 24.289 £ 6 -. 126 1,000 3 1. 7 3 Anisa 1353 CA CYS 197 3979 4543 3 53 3 -39 721-1 7 2 6 ATÓM 1354 C CYS 197 6.803 25.412 7C.124 1,000 5.58 Anisa 1354 C CYS 197 4213 4819 4486 -480 1126 - 2 2 7 2 ATÓM 1355 0 CYS 197 7.917 25.939 7C.175 1,000 3 1.34 Anisa 1355 0 CYS 197 3817 4845 3246 36 -383-9 9 2 ATÓM 1356 CB CYS 197 6.940 22.962 69.767 1,000 3 5.79 Anisa 1356 CB CYS 197 5913 4705 2980 284 1567 - 1 4 2 3 ATÓM 1357 SG CYS 197 6.553 21.535 68741 1,000 8.53 Anisa 1357 SG CYS 197 3605 4224 3009 50 -5 -452 ATÓM 1358 N ALA 198 5.771 25.791 70866 1,000 7.27 Anisa 1358 N ALA 198 5038 4984 4139 -421 1647 -2 06 0 ATÓM 1359 CA ALA 198 5.983 26.811 71888 1,000 3 5.91 Anisa 1359 CA ALA 198 6273 4144 3230 910 522 -1230 ATÓM 1360 C ALA 198 6993 26.328 72921 1,000 4.30 Anisa 1360 C ALA 198 5998 6138 4696 -193 -199 3 3 ATÓM 1361 0 ALA 198 7.759 27.127 73457 1,000 4 2.85 Anisa 1361 0 ALA 198 5209 6328 4742 7,490 - 5 5 5 ATÓM 1362 CB ALA 198 4671 27.231 72532 1,000 4 1.70 Anisa 1362 CB ALA 198 7588 5697 2557 2355 1068-7 2 1 ATÓM 1363 N ASN 199 7.036 25.036 73225 1,000 3 4.93 Anisa 1363 N ASN 199 4027 5975 32 70 805 167 - 6 1 1 ATÓM 1364 CA ASN 199 7.969 24.578 74264 1,000 33.58 Anisa 1364 CA ASN 199 3643 6167 29 50 -670 -265 - 8 0 8 ATÓM 1365 C ASN 199 9352 24.262 73718 1,000 3 1.53 Anisa 1365 C ASN 199 4077 5048 2853 384 -420-8 5 5 ATÓM 1366 0 ASN 199 10.153 23.667 74467 1,000 6.33 Anisa 1366 0 ASN 199 4223 5624 3 9 57 -403 -1305 - 1 2 7 ATÓM 1367 CB ASN 199 7.441 23308 74.929 1,000 6.38 Anisa 1367 CB ASN 199 4533 5029 4 2 62 859 585 - 5 2 2 ATÓM 1368 CG ASN 199 7198 22.180 73 .952 1,000 3 1.28 Anisa 1368 CG ASN 199 4030 4863 2993 882 202 178 ATÓM 1369 OD1 ASN 199 7743 22.151 72 853 1,000 7.62 Anisa 1369 OD1 ASN 199 4693 6272 3 3 3 0 122 728 - 5 7 ATÓM 1370 ND2 ASN 199 6.393 21.190 74 314 1,000 6.42 Anisa 1370 ND2 ASN 199 3508 6251 4 07 8 -13 1133 - 9 5 8 ATÓM 1371 N GLY 200 9616 24.569 72449 1,000 30.93 Anisa 1371 N GLY 200 4342 4232 317 9 436 144-6 9 2 ATÓM 1372 CA GLY 200 10.920 24.304 71866 1,000 5.26 Anisa 1372 CA GLY 200 4 4 30 4905 4060 -317 480 - 2 3 0 0 ATÓM 1373 C GLY 200 11.184 22nd 886 71.429 1,000 6.83

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

Anisa 1373 C GLY 200 4683 4 3 75 4936 -360 1601 - 1 4 6 1 ATÓM 1374 ABOUT GLY 200 12.257 22.566 70897 1. 000 3-2 -., 7 1 Anisa 1374 ABOUT GLY 200 3921 4072 4436 -377,752 - 1 4 0 0 ATÓM 1375 N PHE 201 10.264 21.939 71 588 1: 000 2 8.6 7 Anisa 1375 N PHE 201 3813 4229 2847 14 5 4 62 - 3 2 7 ATÓM 1376 C A PHE 201 10.491 20.575 71106 1,000 2 7.5 5 Anisa 1376 C A PHE 201 3190 4337 2943 -233 219 - 6 7 2 ATÓM 1377 C PHE 201 10.752 20.553 69.600 1. 000 2 4.8 9 Anisa 1377 C PHE 201 2943 3682 2832 190 -263 3 7 9 ATÓM 1378 ABOUT PHE 201 9.994 21.255 68910 1,000 2 8.2 2 Anisa 1378 ABOUT PHE 201 3583 3184 3957 10 -421 277 ATÓM 1379 CB PHE 201 9.250 19.729 71.413 1,000 3 0.4 6 Anisa 1379 CB PHE 201 3153 4862 3560 -371 -40- 7 3 ATÓM 1380 CG PHE 201 9425 18.262 71027 1,000 3 4.8 9 Anisa 1380 CG PHE 201 4015 4609 4632 -775 162 8 9 ATÓM 1381 CD1 PHE 201 10.395 17.472 71605 1.000 3 1.1 8 Anisa 1381 CD1 PHE 201 3436 4103 4310 -875 -93 -1105 ATÓM 1382 CD2 PHE 201 8613 17.681 70078 1. . 000 2 8.8 4 Anisa 1382 CD2 PHE 201 2979 4019 3960 329 612 - 1 0 6 ATÓM 1383 CE1 PHE 201 10.564 16.160 71240 1,000 3 7.7 3 Anisa 1383 CE1 PHE 201 6489 3608 4239 -1078 - 1475 - 5 0 0 ATÓM 1384 CE2 PHE 201 8761 16.363 69679 1,000 3 1.7 8 Anisa 1384 CE2 PHE 201 4327 3911 3838 652 250 1 9 ATÓM 1385 CZ PHE 201 9755 15.606 70.265 1,000 2 9.7 8 Anisa 1385 CZ PHE 201 3705 3397 4211 6 -639 - 8 4 9 ATÓM 1386 N VAL 202 11.706 19.751 69144 1.000 23.51 Anisa 1386 N VAL 202 2671 3392 2868 -292 -1-5 5 7 8 ATÓM 1387 CA VAL 202 11.969 19.626 67706 1,000 2 6.3 7 Anisa 1387 CA VAL 202 3025 4050 2946 -667 57-7 2 4 ATÓM 1388 C VAL 202 11.423 18.283 67198 1,000 2 2.7 5 Anisa 1388 C VAL 202 2729 3348 2567 96 -120 - 3 4 5 ATÓM 1389 ABOUT VAL 202 11.880 17.190 67541 1,000 2 8.7 1 Anisa 1389 ABOUT VAL 202 3249 3799 3859 118 31 6 6 1 ATÓM 1390 CB VAL 202 13.476 19.721 67415 1,000 2 4.9 9 Anisa 1390 CB VAL 202 3060 3427 3008 -277 283 1 5 2 ATÓM 1391 CG1 VAL 202 13.715 19.464 65938 1,000 2 7.7 0 Anisa 1391 CG1 VAL 202 4642 2577 3307 87 1014-3 ATÓM 1392 CG2 VAL 202 14.050 21.071 67823 1,000 2 6.8 0 Anisa 1392 CG2 VAL 202 2826 3868 3487 -490,474 - 3 9 8 ATÓM 1393 N SER 203 10.405 18.402 66333 1,000 2 4.1 0 Anisa 1393 N SER 203 2194 3607 3356 -31 -179 5 5 8 ATÓM 1394 CA SER 203 9634 17.231 65.940 1,000 2 3.70 Anisa 1394 CA SER 203 2373 3584 3046 -290 308-5 5 3 3 ATÓM 1395 C SER 203 10.168 16.511 64.710 1,000 2 1.2 8 Anisa 1395 C SER 203 2173 3041 2871 47 227 - 4 2 ATÓM 1396 ABOUT SER 203 10.159 15.285 64.640 1,000 2 7.6 0 Anisa 1396 ABOUT SER 203 4105 3097 3284 - 482 1010 - 2 4 9 ATÓM 1397 CB SER 203 8.148 17.571 65685 1,000 2 9.0 6 Anisa 1397 CB SER 203 2251 3790 5001 -180 203 -2064 ATÓM 1398 OG SER 203 7584 18.175 66843 1,000 3 2.5 5 Anisa 1398 OG SER 203 3840 4298 4231 919 1099 - 3 8 2 ATÓM 1399 N LEU 204 10688 17.233 63.724 1,000 2 2.4 6 Anisa 1399 N LEU 204 2476 3013 3043 79,450 - 4 6 ATÓM 1400 CA LEU 204 11.166 16.530 62544 1,000 2 0.2 6 Anisa 1400 CA LEU 204 2200 2831 2667 -18 - 1 5 ATÓM 1401 C LEU 204 12.595 16.038 62.747 1,000 1 8.8 3 Anisa 1401 C LEU 204 2151 2528 2477 -75 60-1 ATÓM 1402 0 LEU 204 13.443 16.783 63.251 1,000 2 0.4 7 Anisa 1402 ABOUT LEU 204 2333 2386 3059 -303 -195 4 0 5 ATÓM 1403 CB LEU 204 11.103 17.486 61362 1.000 2 1.4 2 Anisa 1403 CB LEU 204 2718 2 54 8 2871 311 -16-8

SUBSTTIUTE SHEET (RULE 25)

WO 99/33944

PCT / GB98'038 (> 0

ATÓM 14 0 4 CG LEU 2 0'5 9. 7 é 9 1S. 1S3 61.07 9 1. 000 3 3.57 Anisa 14 04 CG LEU 204 2820 4319 5617 177 -iJ16 117 2 ATÓM 1405 CD1 LEU 204 9 .797 18.747 59.660 1. 000 6.19 Anisa 1405 CD1 LEU 204 4402 3807 5540 1276 -1167 9 N 7 ATÓM 1406 CD2 LEU 204 8.581 17.234 61219 1. 000 7.76 Anisa 1406 CD2 LEU 204 3058 5328 5960 -526 -1896 686 ATÓM 1407 N GLN 205 12.864 14.836 62284 1,000 2 0.33 Anisa 1407 N GLN 205 2518 2644 2563 104 -31- 1 2 9 ATÓM 1408 C Ä GLN 205 14. 209 14.247 62335 1,000 18.88 Anisa 1408 C A GLN 205 2522 2225 242 5 -6 -181 3 7 ATÓM 1409 C GLN 205 14.512 13.504 61036 1,000 18:19 Anisa 1409 C GLN 205 1986 2383 2543 -143 -188-8 0 ATÓM 1410 ABOUT GLN 205 13. 577 13.033 60408 1,000 19.87 Anisa 1410 ABOUT GLN 205 1974 3063 2514 -125 -212 - 2 4 7 ATÓM 1411 CB GLN 205 14.296 13.267 63493 1,000 4.25 Anisa 1411 CB GLN 205 3948 2716 2 54 8 202 -343 2 9 7 ATÓM 1412 CG GLN 205 14.164 13.948 64.856 1,000 3 0.64 Anisa 1412 CG GLN 205 4099 5159 2 332 850 -327 - 8 9 ATÓM 1413 CD GLN 205 14.744 13.078 65948 1,000 8.28 Anisa 1413 CD GLN 205 4473 3633 2 64 0 -161 -1015 -390 ATÓM 1414 OE1 GLN 205 14.307 11.921 66041 1,000 3 7.69 Anisa 1414 OE1 GLN 205 5733 5073 35.15 -2,145 -699 478 ATÓM 1415 NE2 GLN 205 15.710 13.553 66711 1,000 4 0.53 Anisa 1415 NE2 GLN 205 6798 4417 4185 -1341 -2865 323 ATÓM 1416 N ALA 206 15.752 13.471 60576 1,000 18:52 Anisa 1416 N ALA 206 2070 2199 2769 -240 -13 4 ATÓM 1417 CA ALA 206 16.152 12.700 59.405 1,000 18:42 Anisa 1417 CA ALA 206 2074 2351 2575 -100 -158 2 3 ATÓM 1418 C ALA 206 17.343 11.802 59.738 1,000 17:41 Anisa 1418 C ALA 206 2107 2158 2350 -185 -254-1 7 ATÓM 1419 ABOUT ALA 206 18.123 12.203 60613 1,000 2 0.67 Anisa 1419 ABOUT ALA 206 2469 2410 2 97 3 -48 -711- 3 9 6 ATÓM 1420 CB ALA 206 16.637 13.599 58.270 1,000 18.77 Anisa 1420 CB ALA 206 2119 2310 2 703 156 -65 147 ATÓM 1421 N GLU 207 17.492 10.764 58931 1,000 18:09 Anisa 1421 N GLU 207 2092 2101 2680 -249 -496-1 6 6 ATÓM 1422 C A GLU 207 18.710 9944 58.966 1,000 19:48 Anisa 1422 CA GLU 207 2210 2091 31C0 -73 -432-4 4 ATÓM 1423 C GLU 207 19.851 10.730 58.320 1,000 19.98 Anisa 1423 C GLU 207 2018 2233 3342 220 -560 544 ATÓM 1424 ABOUT GLU 207 19.732 11.068 57.143 1,000 2 0.33 Anisa 1424 ABOUT GLU 207 2000 2753 2970 -471 8 9 ATÓM 1425 CB GLU 207 18.566 8623 58.214 1,000 2 4.03 Anisa 1425 CB GLU 207 3401 1784 3946 316 -1226 6 1 ATÓM 1,426 CG GLU 207 19757 7.674 58295 1,000 4.35 Anisa 1,426 CG GLU 207 3223 1907 4121 354 92 4 6 7 ATÓM 1427 CD GLU 207 20.730 7791 57.129 1,000 3 1.69 Anisa 1427 CD GLU 207 2729 5178 4134 -1218 -176 12 2 ATÓM 1428 OE1 GLU 207 20.376 7.611 55.943 1,000 6.97 Anisa 1428 OE1 GLU 207 2849 3404 3993 31 -256 309 ATÓM 1429 OE2 GLU 207 21.908 8.121 57407 1,000 3 0.70 Anisa 1429 OE2 GLU 207 2484 3416 5764 -233 -342-1 ATÓM 1430 N VAL 208 20.919 10.936 59078 1,000 18:53 Anisa 1430 N VAL 208 2020 2112 2907 130 -362 320 ATÓM 1431 CA VAL 208 22.150 11.547 58.541 1,000 19:53 Anisa 1431 C A VAL 208 2044 2238 3137 39 -476,630 ATÓM 1432 C VAL 208 23.341 10.755 59.088 1,000 2 1.95 Anisa 1432 C VAL 208 2040 2792 3507 225 -461 797 ATÓM 1433 ABOUT VAL 208 23.460 10.663 60.314 1,000 2 3.82 Anisa 1433 ABOUT VAL 208 2262 3240 3547 -40 -858 825 ATÓM 1434 C B VKL 208 22.271 13.027 58.905 1,000 19.72

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98O3860 • 60-

Amis 1434 CB VAL 20S 1918 24 2 9 3 14 5 -4 7 -3 0S 3 1 1 ATÓM 1435 CG1 VAL 208 23 .524 13. 62o 58281 1. 000 S> K Anisa 1435 CG1 VAL 208 2524 2 374 3895 -202 284 349 ATÓM 1436 CG2 VAL 208 21.030 13.812 58.469 I. 000 19:47 Anisa 1436 CG2 VAL 208 2 4 62 2279 2658 232 -ob7 - S 7 ATÓM 1437 N GLY 209 24. 180 10.169 58.246 1. 000 2 3.8 = Anisa 1437 N GLY 209 2500 2449 4123 465 -711 3 z ATÓM 1438 C A GLY 209 25.306 9 .374 58.773 1,000 6.42 Anisa 1438 CA GLY 209 1987 3 599 44 5 0 ·; 460 -487 516 ATÓM 1439 C GLY 209 24.905 8,250 59695 1. 000 3 0.0i Anisa 1439 C GLY 209 3469 3240 4693 238 -1422 732 ATÓM 1440 0 GLY 209 25.609 7.835 60629 1,000 3 1.45 Anisa 1440 0 GLY 209 4053 4458 3438 1225 -897 8 3 ATÓM 1441 N GLY 210 23691 7.702 59.523 1,000 6.64 Anisa 1441 N GLY 210 3165 3214 3744 259 -86 350 ATÓM 1442 C A GLY 210 23263 6. 585 60.360 1,000 2 9. 7 S Anisa 1442 C A GLY 210 4603 3091 3619 -55 -997 584 ATÓM 1443 C GLY 210 22.622 6993 61663 1,000 8.28 Anisa 1443 C GLY 210 5827 4212 4507 -2,536 733 5 0 ATÓM 1444 0 GLY 210 22.160 6187 62481 1,000 4 1.45 Anisa 1444 0 GLY 210 4152 6516 5082 -1874 -568 2 3 4 6 ATÓM 1445 N ALA 211 22.512 8.274 61.976 1,000 3 2.81 Anisa 1445 N ALA 211 4803 4625 3037 1372 -1177 632 ATÓM 1446 CA ALA 211 21.828 8.603 63235 1,000 3 5.62 Anisa 1446 CA ALA 211 3993 5958 3584 1061 -610 970 ATÓM 1447 C ALA 211 20.663 9.543 62940 1,000 3 1.43 Anisa 1447 C ALA 211 3508 4737 3699 302 69 1854 ATÓM 1448 0 ALA 211 20.652 10.097 61858 1,000 8.28 Anisa 1448 0 ALA 211 3661 4062 3020 -571 -552 10 10 ATÓM 1449 CB ALA 211 22.812 9278 64.170 1,000 4 1.36 Anisa 1449 CB ALA 211 3644 8904 3169 1372 -18-7 9 1 ATÓM 1450 N PHE 212 19.682 9.676 63.825 1,000 6.68 Anisa 1450 N PHE 212 5211 4237 4489 1166 1266 2 1 7 1 ATÓM 1451 CA PHE 212 18.620 10.654 63641 1,000 8.82 Anisa 1451 CA PHE 212 4490 3167 3293 263 503 1 0 3 7 ATÓM 1452 C PHE 212 19.100 12.023 64124 1,000 3 4.72 Anisa 1452 C PHE 212 6746 3760 2685 -248 -539 776 ATÓM 1453 0 PHE 212 19.667 12.191 65.210 1,000 3 9.12 Anisa 1453 0 PHE 212 6144 5384 3335 -549 -1128 1 2 2 0 ATÓM 1454 CB PHE 212 17.358 10.219 64388 1,000 5.35 Anisa 1454 CB PHE 212 6376 2569 8288 1348 3747 2 3 1 4 ATÓM 1455 N THR 213 18.906 13.008 63.271 1,000 2 6.30 Anisa 1455 N THR 213 4134 2738 3122 662 -581 100 ATÓM 1456 CA THR 213 19.424 14.359 63433 1,000 25.08 Anisa 1456 CA THR 213 3587 2852 3089 767 -810 - 3 2 ATÓM 1457 C THR 213 18.190 15.283 63.400 1,000 2 3.81 Anisa 1457 C THR 213 2835 2652 3560 215 -855- 6 4 3 ATÓM 1458 0 THR 213 17.329 15.137 62517 1,000 2 1.40 Anisa 1458 0 THR 213 2640 2269 3223 -328 -580-1 7 9 ATÓM 1459 CB THR 213 20.398 14,759 62308 1,000 2 7.60 Anisa 1459 CB THR 213 3155 3220 4113 189 -356-7 9 8 ATÓM 1460 OG1 THR 213 21.673 14.084 62.374 1,000 3 2.00 Anisa 1460 OG1 THR 213 3582 4220 4356 746 -410 520 ATÓM 1461 CG2 THR 213 20.735 16.254 62355 1,000 9.45 Anisa 1461 CG2 THR 213 4422 3320 3448 -106 -1265 - 2 0 3 ATÓM 1462 N ASP 214 18.119 16.177 64371 1,000 2 1.05 Anisa 1462 N ASP 214 2790 2236 2972 -82 -380-1 ATÓM 1463 CA ASP 214 17.001 17.110 64462 1,000 2 0.61 Anisa 1463 CA ASP 214 2742 2095 2993 -117 -898- 3 7 9 ATÓM 1464 C ASP 214 16.994 18.030 63 .226 1. 000 2 0.58 Anisa 1464 C ASP 2 14 2373 2525 2923 182 -169 - 2 4 7

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98O3S60

-61 ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANIS ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM

6 5 14 6 5 14 6 ó

1466

1467

1467

1468

1468

1469

1469

1470

1470

1471

1471

1472

1472

1473

1473

1474

1474

1475

1475

1476

1476

1477

1477

1478

1478

1479

1479

1480

1480

1481

1481

1482

1482

1483

1483

1484

1484

1485

1485

1486

1486

1487

1487

1488

1488

1489

1489

1490

1490

1491

1491

1492

1492

1493

1493

1494 14 94

1495

"WITH ASP 2 1 4 18.018 1S. 430 ó 2. 6 7 S 1. 00G 2 3.0? 0 ASP 2 14 2461 2883 3 4 0 š -167 -W. , - 5 7 2 CB ASP 214 17205 18 .058 65637 1. 000 3.54 CB ASP 214 3304 2607 3 03? -92 -748-6 N CG ASP 214 16.915 17.506 67004 1,000 2 4.93 CC- ASP 2 14 3545 2850 3 07 9 450 -417 -614 OD1 ASP 214 16.357 16.395 67113 1. 000 9.17 OD1 ASP 214 4134 3070 3878 202 -705 262 OD2 ASP 214 17.276 18.191 67.990 1. 000 3 4.36 OD2 ASP 214 6917 3040 3107 1017 -1412 - 7 3 6 N LEU 215 15.802 18.452 62859 1. 000 2 0.74 N LEU 215 2426 2372 3081 86 -60 306 C A LEU 215 15.568 19.401 61796 1,000 2 0.55 CA LEU 215 2895 2013 2899 -202 -178 141 C LEU 215 14.724 20.552 62332 1,000 2.19 C LEU 215 2482 2240 2504 -142 -34 321 0 LEU 215 13 .510 20.613 62142 1,000 2.39 0 LEU 215 2635 2483 3389 -160 -475 5 7 4 CB LEU 215 14.826 18.722 60650 1,000 2 2.04 CB LEU 215 2778 2510 3086 -140 -261 - 6 CG LEU 215 15.598 17.502 60128 1,000 5.25 CG LEU 215 3680 2829 3085 85 -166 -402 CD1 LEU 215 14.680 16.736 59.174 1,000 7.12 CD1 LEU 215 4886 2934 2482 419 -1128 - 6 May CD2 LEU 215 16.881 18.046 59510 1,000 3 0.76 CD2 LEU 215 3434 3089 5165 1003 524 561 N PRO 216 15.383 21.433 63078 1,000 19.68 N PRO 216 2407 2191 2879 -157 148 10 3 C A PRO 216 14.665 22.534 63708 1,000 2.42 CA PRO 216 2869 2812 2836 272 10 - 2 3 8 C PRO 216 14.201 23.576 62698 1,000 5.36 C PRO 216 4118 2433 3086 566 -131 - 3 1 4 0 PRO 216 14,700 23.759 61536 1,000 2 4.67 0 PRO 216 3682 2406 3284 187 -176-2 6 CB PRO 216 15.693 23.092 64676 1,000 2 3.88 CB PRO 216 3108 3049 2917 -216 116-318 CG PRO 216 17.033 22.701 64146 1,000 8.31 CG PRO 216 2994 2996 4766 -88 -117 -1454 CD PRO 216 16.807 21.405 63436 1,000 2 4.55 CD PRO 216 2353 1777 5197 -436 -83- 3 4 8 N TYR 217 13.154 24.287 63102 1,000 4.13 N TYR 217 3237 2704 3229 244 -631-5 5 1 1 CA TYR 217 12.676 25.510 62462 1,000 2 6.08 CA TYR 217 2514 2899 4498 104 -592 3 9 C TYR 217 13.824 26.516 62369 1,000 5.24 C TYR 217 3049 2948 3592 -257 -506 - 5 3 8 0 TYR 217 14.570 26.675 63340 1,000 3 1.78 0 TYR 217 4114 2863 5096 -352 -2151 564 CB TYR 217 11.559 26.103 63315 1,000 2 5.97 CB TYR 217 2747 2773 4346 86 -615 16 16 CG TYR 217 11.189 27543 63.125 1,000 3 1.64 CG TYR 217 3080 2803 6139 338 - 1473 - 6 4 4 CD1 TYR 217 10.430 27,928 62022 1,000 7.85 CD1 TYR 217 2238 3029 5314 511 -176 9 3 CD2 TYR 217 11.512 28.522 64069 1,000 8.49 CD2 TYR 217 472 1 2813 7093 -686 -1681 - 7 4 9 CE1 TYR 217 10.021 29.219 61772 1,000 6.53 CE1 TYR 217 1908 2675 5496 -41 107 6 9 CE2 TYR 217 11.113 29.835 63827 1,000 4 2.90 CE2 TYR 217 7112 2347 6842 -1415 -1949 - 2 1 7 CZ TYR 217 10.373 30.168 62712 1. 000 3 4.93

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

Anisa 1495 CZ TYR 217 4042 2 74 7 6483 -1462 -545 1 6 ó ATÓM 1496 OH TYR 217 9.996 31.4S6 62473 1. 000 > 4 1 Anisa 1496 OH TYR 217 5499 2895 54 3 9 -753 -250-2 8 9 ATÓM 1497 N ARG 218 14.022 27.110 61218 Γ. 000 5.58 Anisa 1497 N ARG 218 3461 2406 3852 -227 -533 - 4 7 7 ATÓM 1498 C A ARG 218 14.923 28.243 61049 1,000 9.26 Anisa 1498 C A ARG 218 3630 3270 4219 -784 -1349 266 ATÓM 1499 C ARG 218 14.113 29.336 60365 1,000 2 4.81 Anisa 1499 C ARG 218 4063 2949 2415 -382 -228 - 5 6 ATÓM 1500 ABOUT ARG 218 13. 746 29.174 59212 1,000 9.56 Anisa 1500 ABOUT ARG 218 6298 2267 2666 -890 -994 165 ATÓM 1501 CB ARG 218 16.162 27.823 60256 1,000 3 5.90 Anisa 1501 CB ARG 218 3223 3685 6732 -624 -703 896 ATÓM 1502 CG ARG 218 17.369 28.665 60.661 1,000 5 1.38 Anisa 1502 CG ARG 218 4740 6768 8015 -3,031 430 - 1 7 3 ATÓM 1503 CD ARG 218 18.539 28.606 59701 1,000 8.84 Anisa 1503 CD ARG 218 4968 6308 3482 -3,596 -1166 1 6 4 7 ATÓM 1504 NE ARG 218 19.343 27.395 59.905 1,000 4 5.09 Anisa 1504 NE ARG 218 4655 7495 4982 -2325 -962-9 4 ATÓM 1505 CZ ARG 218 20.272 27208 58959 1,000 5.53 Anisa 1505 CZ ARG 218 5299 11458 4340 -2,701 -1187 - 1 9 4 8 ATÓM 1506 NH1 ARG 218 20.289 28.158 58031 1,000 6 0.85 Anisa 1506 NH1 ARG 218 2399 16648 4071 -1943 -1333 548 ATÓM 1507 NH2 ARG 218 21.060 26.165 59.001 1,000 6 0.37 Anisa 1507 NH2 ARG 218 8580 10111 4247 -2152 639 -4241 ATÓM 1508 N PRO 219 13.871 30,496 60972 1,000 2 5.89 Anisa 1508 N PRO 219 2625 4126 3086 35,296 -1014 ATÓM 1509 CA PRO 219 13.065 31.548 60326 1,000 2 8.10 Anisa 1509 CA PRO 219 2828 3120 4730 -410 379-6 9 6 ATÓM 1510 C PRO 219 13.636 31.959 58.981 1,000 8.43 Anisa 1510 C PRO 219 3141 3010 4653 -190 116 -328 ATÓM 1511 ABOUT PRO 219 12.904 32.393 58.081 1,000 4.17 Anisa 1511 ABOUT PRO 219 4734 3500 4750 302 -798-8 9 3 ATÓM 1512 CB PRO 219 13.115 32.717 61316 1,000 9.70 Anisa 1512 CB PRO 219 5621 3612 5852 -500 1615 -1527 ATÓM 1513 CG PRO 219 13.368 32.033 62628 1,000 4 2.38 Anisa 1513 CG PRO 219 6139 5277 4688 -257 2084 - 20 08 6 ATÓM 1514 CD PRO 219 14.370 30943 62289 1,000 3 2.77 Anisa 1514 CD PRO 219 3901 5719 2831 -602 828 -1603 ATÓM 1515 N ASP 220 14.950 31.824 58.811 1,000 2 5.65 Anisa 1515 N ASP 220 3328 1582 4837 -276 801 - 8 7 8 ATÓM 1516 CA ASP 220 15.590 32.280 57587 1,000 6.45 Anisa 1516 CA ASP 220 3594 2115 4341 -782 248-8 6 1 ATÓM 1517 C ASP 220 15.781 31.305 56451 1,000 8.46 Anisa 1517 C ASP 220 3549 1843 5423 -111 1638-9 4 3 ATÓM 1518 ABOUT ASP 220 16.432 31.620 55433 1,000 2 5.80 Anisa 1518 ABOUT ASP 220 3249 2021 4533 -140 622 - 4 1 2 ATÓM 1519 CB ASP 220 16.911 32.962 57.998 1,000 3 3.76 Anisa 1519 CB ASP 220 2351 3539 6938 -445 1188 - 1 7 2 4 ATÓM 1520 CG ASP 220 17.882 31.913 58.502 1,000 4 2.36 Anisa 1520 CG ASP 220 2653 353 1 9912 -812 230-9 5 7 ATÓM 1521 OD1 ASP 220 17.484 31. 170 59.423 1,000 3 7.00 Anisa 1521 OD1 ASP 220 3154 4148 6757 -104 -410-2001 ATÓM 1522 OD2 ASP 220 18.981 31.787 57957 1,000 7.34 Anisa 1522 OD2 ASP 220 2520 4700 6969 93 - 824 - 1 2 6 6 ATÓM 1523 N ALA 221 15.292 30.072 56.537 1,000 4.79 Anisa 1523 N ALA 221 4148 1872 3398 -252 671 - 6 6 9 ATÓM 1524 CA ALA 221 15.695 29.016 55.596 1,000 19:17 Anisa 1524 CA ALA 221 2165 1868 3251 -52 -92 - 6 0 0 ATÓM 1525 C ALA 221 14.551 27.996 55.479 1,000 18.60 Anisa 1525 C ALA 221 1920 2238 2908 -82 -207-3 3 6 2

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / G Β98Ό3860

ATÓM 1526 0 ALA ΑΝI SOU 1526 0 ALA ATÓM 1527 CB ALA Anisa 1527 CB ALA ATÓM 1528 N VAL Anisa 1528 N VAL ATÓM 1529 C A VAL Anisa 1529 CA VAL ATÓM 1530 C VAL Anisa 1530 C VAL ATÓM 1531 0 VAL Anisa 1531 0 VAL ATÓM 1532 CB VAL Anisa 1532 CB VAL ATÓM 1533 CG1 VAL Anisa 1533 CG1 VAL ATÓM 1534 CG2 VAL Anisa 1534 CG2 VAL ATÓM 1535 N LEU Anisa 1535 N LEU ATÓM 1536 CA LEU Anisa 1536 CA LEU ATÓM 1537 C LEU Anisa 1537 C LEU ATÓM 1538 0 LEU Anisa 1538 0 LEU ATÓM 1539 CB LEU Anisa 1539 CB LEU ATÓM 1540 CG LEU Anisa 1540 CG LEU ATÓM 1541 CD1 LEU Anisa 1541 CD1 LEU ATÓM 1542 CD2 LEU Anisa 1542 CD2 LEU ATÓM 1543 N VAL Anisa 1543 N VAL ATÓM 1544 CA VAL Anisa 1544 CA VAL ATÓM 1545 C VAL Anisa 1545 C VAL ATÓM 1546 0 VAL Anisa 1546 0 VAL ATÓM 1547 CB VAL Anisa 1547 CB VAL ATÓM 1548 CG1 VAL Anisa 1548 CG1 VAL ATÓM 1549 CG2 VAL Anisa 1549 CG2 VAL ATÓM 1550 N PHE Anisa 1550 N PHE ATÓM 1551 C A PHE Anisa 1551 CA PHE ATÓM 1552 C PHE Anisa 1552 C PHE ATÓM 1553 ABOUT PHE Anisa 1553 0 PHE ATÓM 1554 CB PHE Anisa 1554 CB PHE ATÓM 1555 CG PHE Anisa 1555 CG PHE ATÓM 1556 CD1 PHE

221 13.763 27852 56415 1,000 6.47 22 1 4 127 264 1 3 2 8 8 -1307 8 · 9 <- 9 0 4 221 16.939 28.316 56.104 1. 000 19:36 221 2054 2333 2 96 9 -5 3 7 -316 6 6 222 14.490 27.385 54.313 1,000 17:35 222 2089 1841 2 661 -101 -323-1 1 5 4 222 13.556 26276 54083 1,000 17:45 222 1620 2004 3004 -66 -417 1 9 222 14.333 24.965 54077 1,000 15.69 222 1616 1876 247 1 -269 -349 - 3 222 15.512 24.934 53 .716 1,000 17.84 222 1658 1730 33s0 -108 -195 4 8 222 12.822 26.433 52.747 1,000 19.60 222 2267 2202 2979 91 - 666 - 3 0 4 222 13.781 26.363 51.563 1,000 2 1.96 222 2252 3113 2977 250 -645-1 8 2 222 11.730 25.411 52490 1,000 2.44 222 2923 2537 3067 -497 -898 4 4 223 13.789 23.892 54.621 1,000 16:30 223 1792 1694 2706 -239 -93-5 5 3 2 223 14.407 22.575 54.579 1,000 15.91 223 1679 1864 2503 -93 -297 - 3 223 14.114 21.908 53.243 1,000 14.86 223 1337 1537 2773 -141 -322 - 4 5 8 223 12.969 21.888 52766 1,000 16:23 223 1317 2132 2719 -391 - 2 8 1 223 13.829 21.779 55761 1,000 19.97 223 2740 1945 2901 -121 205-2 2 1 2 223 14.298 20.348 55882 1,000 2 3.01 223 2668 1871 4205 -375 -170 9 1 223 15.797 20.322 56143 1,000 2 3.73 223 2570 3067 3378 68 135 3 16 223 13.492 19.668 56.979 1,000 3 5.71 223 2813 3296 7459 525 1115 2 3 3 3 224 15.115 21.370 52.570 1,000 14:18 224 1383 1446 2560 -28 -320 - 2 0 4 224 14.956 20.627 51.330 1,000 14:52 224 1585 1501 2431 -23 -322 - 1 2 7 224 15.320 19.160 51.561 1,000 13:59 224 1464 1522 2178 23 -290-2 2 5 1 224 16.442 18.861 51.981 1,000 15:38 224 1464 1558 2822 0 -505 - 3 6 4 224 15.832 21.209 50.222 1,000 14:25 224 1402 1606 2407 -60 -461-10 10 224 15.685 20.443 48.906 1,000 16.63 224 1682 2164 2474 -159 -408-4 4 2 1 224 15.575 22.687 50.040 1,000 16:40 224 1807 1562 2863 6 -508 8 7 225 14 .340 18.299 51.299 1,000 13:49 225 1494 1526 2106 -66 -353 - 1 2 0 225 14.647 16.882 51.162 1,000 14.67 225 1639 1505 243 1 -115 -61-2 2 8 3 225 14.756 16.533 49.675 1,000 14:27 225 1536 1533 2352 100 -260-1 9 4 225 13.858 16.876 48.893 1,000 16:25 225 1604 2000 2569 296 -311-8 8 225 13.537 15.999 51749 1,000 15:57 225 1613 1563 2740 -25 -46 2 4 225 13.387 15.996 53.257 1. 000 17.95 225 1888 2267 2666 -650 -302 2 0 3 225 14.409 15.809 54157 1,000 7.39

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9SO3860

Anisa 1 5 S ó CD1 PHE 225 2740 4 234 343 1 -910 -1094 cqc ATÓM 1557 CD2 PHE 225 12.125 15.863 53.820 1.000 2 * 1 · ANISO'J 1557 CD2 PHE 225 2333 2765 2917 -166 399 - 5 ATÓM 1558 CE1 PHE 225 14.211 15.673 55521 1.000 2 6. S 2 Anisa 1558 CE1 PHE 225 3108 3657 3424 -1044 -1241 ATÓM 1559 CE2 PHE 225 11.910 15.910 55186 1.000 2 1. ó 5 Anisa 1559 CE2 PHE 225 2994 2414 2817 623,239 -39 ATÓM 1560 CZ PHE 225 12958 15.787 56078 1,000 2 8.8 2 Anisa 1560 CZ PHE 225 3705 3716 353 1 -833 -66 3 3 4 0 ATÓM 1561 N CYS 226 15.795 15.817 49 .266 1. 000 1 2.7 7 Anisa 1561 N CYS 226 1428 1292 2131 -60 -370-2 3 9 ATÓM 1562 CA CYS 226 15.810 15.180 47.956 1,000 1 2.9 9 Anisa 1562 CA CYS 226 1360 1440 2135 12 -356 - 2 0 7 ATÓM 1563 C CYS 226 14.903 13.956 47.985 1.000 1 2.3 7 Anisa 1563 C CYS 226 1533 1212 1955 8 -283-3 3 1 1 ATÓM 1564 ABOUT CYS 226 14.961 13 .217 48.974 1000 1 5. 6 N Anisa 1564 ABOUT CYS 226 1885 1651 2424 -140 -611 ATÓM 1565 CB CYS 226 17.228 14.855 47.527 1,000 1 3.7 7 Anisa 1565 CB CYS 226 1410 1627 2193 19 -203-7 5 ATÓM 1566 SG CYS 226 18.224 16.367 47.314 1.000 16.37 Anisa 1566 SG CYS 226 1744 1740 2735 -222 -236 -1 ATÓM 1567 N GLY 227 14.150 13.722 46.928 1.000 1 3.2 0 Anisa 1567 N GLY 227 1388 1513 2113 -28 -293-2 9 0 ATÓM 1568 CA GLY 227 13.352 12.496 46.899 1,000 1 2.58 Anisa 1568 C A GLY 227 1279 1631 1872 -83 -438 2 5 5 ATÓM 1569 C GLY 227 13.903 11.541 45.849 1,000 1 2.54 Anisa 1569 C GLY 227 1518 1279 1965 15 -288 - 7 8 ATÓM 1570 ABOUT GLY 227 14.917 11.732 45.152 1.000 13.58 Anisa 1570 ABOUT GLY 227 1630 1523 2008 -155 8 2 ATÓM 1571 N ALA 228 13.212 10.400 45.712 1.000 13.02 Anisa 1571 N ALA 228 1490 1306 2151 60 -204 - 1 6 1 ATÓM 1572 CA ALA 228 13.663 9.321 44.860 1.000 12.41 Anisa 1572 CA ALA 228 1649 1155 1912 -68 -119-6 6 3 ATÓM 1573 C ALA 228 13.706 9727 43.404 1.000 12.82 Anisa 1573 C ALA 228 1566 1288 2016 97 -223-5 ATÓM 1574 ABOUT ALA 228 14.482 9.132 42.651 1.000 13.64 Anisa 1574 ABOUT ALA 228 1717 1462 2004 26 -6 -131 ATÓM 1575 CB ALA 228 12.714 8.121 45.058 1.000 1 4.5 6 Anisa 1575 CB ALA 228 1808 1366 2356 -219 358 - 2 3 4 ATÓM 1576 N ILE 229 12,909 10.695 42952 1.000 1 3.6 1 Anisa 1576 N ILE 229 1340 1391 2441 -43 -289 2 7 4 ATÓM 1577 CA ILE 229 13.024 11.131 41.566 1.000 12.93 Anisa 1577 CA ILE 229 1325 1243 2344 -42 -305 1 7 3 ATÓM 1578 C ILE 229 14.342 11.864 41358 1.000 13.17 Anisa 1578 C ILE 229 1327 1364 2311 -47 -192 13 0 ATÓM 1579 ABOUT ILE 229 14.938 11.746 40.262 1.000 1 4.4 1 Anisa 1579 ABOUT ILE 229 1587 1596 2293 -37 -168 1 8 3 ATÓM 1580 CB ILE 229 11.768 11.888 41.103 1.000 1 3.4 6 Anisa 1580 CB ILE 229 1470 1631 2015 171 -354 - 4 2 ATÓM 1581 CG1 ILE 229 10.599 10.920 40973 1,000 1 5.7 2 Anisa 1581 CG1 ILE 229 1218 1936 2817 85 31 118 ATÓM 1582 CG2 ILE 229 12.040 12.674 39808 1,000 1 4.1 9 Anisa 1582 CG2 ILE 229 1670 1425 2298 76 -364 174 ATÓM 1583 CD1 ILE 229 10.745 9.924 39836 1.000 20.03 Anisa 1583 CD1 ILE 229 2129 1814 3667 -208 -385 - 4 8 8 ATÓM 1584 N ALA 230 14.877 12.575 42.353 1.000 13.38 Muso 1584 N ALA 230 1252 1378 2454 -97 -177 7 4 ATÓM 1585 CA ALA 230 16.209 13.185 42.130 1,000 1 2.3 0 Anisa 1585 CA ALA 230 1156 1444 2074 66 - 97 - 1 0 8 ATÓM 1586 C ALA 230 17.223 12.033 41. 976 1.000 12.89 Anisa 1586 C ALA 230 1491 1327 2079 128 30-20

SUBSTTTUTE SHEET (RULE 26) \ WO 99/33994

PCT / GB9S / 03860

ATÓM 1537 ABOUT ALA 2 30 1S.100 12.091 41.146 1,000 1 3 . é 5 Anisa 1587 ABOUT ALA 23 0 1240 1530 2413 103 4 ó ATÓM 1583 C 5 ALA 230 16.583 14,000 43.345 1. 000 1 3 - in .. . e o Anisa 1588 C3 ALA 230 1559 1415 2215 -186 - 2: L - 2 2 9 ATÓM 1589 N THR 23 1 17.143 10.978 4 2.3 0 5 1,000 1 3 . 3 1 Anisa 1589 N THR 231 1526 1318 2214 58 -2i 51 - 1 ATÓM 1590 C A THR 231 18.022 9815 42.659 1,000 1 3 . 3 2 Anisa 1590 CA THR 231 1660 1307 2093 78 -302 3 2 ATÓM 1591 C THR 23 1 17.906 9.224 41.251 1. 000 1 3 . 2 7 Anisa 1591 C THR 231 1300 1631 211 L 205 -211 3 ATÓM 1592 ABOUT THR 231 18. 932 8974 40620 1,000 1 5 . 5 1 Anisa 1592 ABOUT THR 231 1468 1759 2 667 245 58 - 1 6 0 ATÓM 1593 CB THR 231 17.656 8.751 43.688 1,000 1 3 . 0 3 Anisa 1593 CB THR 231 1500 1302 2151 4 ó - 16 6 1 2 ATÓM 1594 OG1 THR 231 17.530 9.313 44.995 1,000 1 4 . 7 0 Anisa 1594 OG1 THR 231 1742 1614 2230 -99 32 - 1 4 ATÓM 1595 CG2 THR 231 18.698 7.621 43.697 1,000 1 3 . 6 9 Anisa 1595 CG2 THR 231 1449 1419 2335 113 -211 197 ATÓM 1596 N LEU 232 16.665 9049 4 0. 9 6 1,000 1 3 . 4 3 Anisa 1596 N LEU 232 1447 1384 227 :. 75 -404 - 2 7 ATÓM 1597 CA LEU 232 16.446 8.396 39.527 1,000 1 4 . 1 1 Anisa 1597 CA LEU 232 1809 1226 232 6 80 -468 4 9 ATÓM 1598 C LEU 232 16.975 9.248 38.381 1,000 1 5 . 5 3 Anisa 1598 C LEU 232 1968 1557 2376 209 -3 9 0 ATÓM 1599 ABOUT LEU 232 17.749 8.808 37.504 1,000 1 7 . 1 6 Anisa 1599 ABOUT LEU 232 2024 1949 2546 107 -116-519 ATÓM 1600 CB LEU 232 14.940 8.135 39.368 1,000 1 4 . 4 7 Anisa 1600 CB LEU 232 1692 1630 217 5 72 -396 - 1 6 1 ATÓM 1601 CG LEU 232 14.525 7.307 38.155 1,000 1 5 . 8 9 Anisa 1601 CG LEU 232 1941 1768 2329 120 -470 - 3 0 4 ATÓM 1602 CD1 LEU 232 15.118 5.920 38.202 1,000 2 3 . 1 9 Anisa 1602 CD1 LEU 232 3565 2020 3 22 8 743 -1110 -851 ATÓM 1603 CD2 LEU 232 13.003 7.190 38.126 1,000 1 9 . 4 6 Anisa 1603 CD2 LEU 232 2006 2262 312 6 -470 -523-6 6 ATÓM 1604 N VAL 233 16.539 10.514 38.2 99 1,000 1 3 . 7 3 Anisa 1604 N VAL 233 1736 1454 2 02 5 -7 -263 19 3 ATÓM 1605 CA VAL 233 16.893 11.317 37.117 1,000 1 3 . 8 4 Anisa 1605 CA VAL 233 1674 1658 192 6 141 -73 107 ATÓM 1606 C VAL 233 18.407 11.510 37.025 1,000 1 4 . 08 Anisa 1606 C VAL 233 1716 1674 195E 72 -46 1 1 3 ATÓM 1607 ABOUT VAL 233 18.940 11.587 35.S10 1,000 1 6 . 6 5 Anisa 1607 ABOUT VAL 233 1923 2325 2 07 9 38 109 4 0 1 ATÓM 1608 CB VAL 233 16.098 12.626 37062 1,000 1 4 . 69 Anisa 1608 CB VAL 233 1680 1696 2206 141 -165 333 ATÓM 1609 CG1 VAL 233 16.529 13.650 38.113 1,000 1 5 . 7 0 Anisa 1609 CG1 VAL 233 1615 1654 2 696 34 156 - 2 8 ATÓM 1610 CG2 VAL 233 16.117 13.206 35.647 1,000 1 6 . 4 3 Anisa 1610 CG2 VAL 233 1740 2041 2 45 9 251 117 596 ATÓM 1611 N THR 234 19.100 11.594 38.175 1,000 1 4 . 2 3 Anisa 1611 N THR 234 1599 1724 2083 146 -110 235 ATÓM 1612 CA THR 234 20.524 11.908 38.148 1,000 1 6 . 1 4 Anisa 1612 CA THR 234 1664 1868 2602 63 -171 - 4 9 ATÓM 1613 C THR 234 21.346 10.621 38.006 1,000 1 7 . 0 9 Anisa 1613 C THR 234 1717 1865 2912 146 211-5 5 1 ATÓM 1614 ABOUT THR 234 22.558 10.644 38.139 1,000 1 7 . 2 5 Anisa 1614 ABOUT THR 234 1776 1951 2 82 6 108 200 229 ATÓM 1615 CB THR 234 21.030 12.681 39.373 1,000 1 5 . 2 9 Anisa 1615 CB THR 234 1667 1502 2 64 2 -46 -149 1 6 4 ATÓM 1616 OG1 THR 234 20.849 11.819 40.522 1,000 1 5 . 4 5 Anisa 1616 OG1 THR 2 34 1659 1708 2502 -80 59 4 4 ATÓM 1617 CG2 THR 234 20.291 13.978 39.597 1,000 1 6 . 6 1

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S'03860

ANISOU 1617 CG1 THR 234 1564 -66- 1672 3 077 3 -34-4 4 2 ATÓM 1618 N GLY 235 20.712 9441 37.833 1. 000 LŤ.8 0 Anisa 1618 N GLY 235 1905 1914 2564 193 2 = - 2 9 ATÓM 1619 C A GLY 235 21.484 8209 37.792 1. 000 1 b. 1 0 Anisa 1619 C A GLY 235 2049 1861 2586 133 223 - 4 8 8 ATÓM 1620 C GLY 235 22.225 7931 39083 1,000 1 á. 0 6 Anisa 1620 C GLY 235 2046 2049 2768 419 4 99 3 0 3 ATÓM 1621 ABOUT GLY 235 23.285 7289 39. 010 1. 000 1.26 Anisa 1621 ABOUT GLY 235 2167 2606 3303 679 3 4 3 - 7 4 ATÓM 1622 M GLY 236 21.602 8.149 40.237 1,000 1 ó. 1 7 Anisa 1622 N GLY 236 1663 1901 2582 36 291 305 ATÓM 1623 C A GLY 236 22.080 7673 41.520 1,000 17:27 Anisa 1623 C A GLY 236 2135 1671 2754 225 2 S 2 2! 9 ATÓM 1624 C GLY 236 23033 8.639 42 .194 1,000 16.88 Anisa 1624 C GLY 236 1880 1890 2644 204 100 2 2 2 ATÓM 1625 ABOUT GLY 236 23.692 8272 43 .193 1,000 19:42 Anisa 1625 ABOUT GLY 236 2165 2399 2814 314 -90 4 1 9 ATÓM 1626 N GLN 237 23.134 9.890 41. 746 1,000 16.99 Anisa 1626 N GLN 237 1647 1851 2957 213 -213 1 6 7 ATÓM 1627 CA GLN 237 24.074 10.849 42 .298 1,000 16.75 Anisa 1627 CA GLN 237 1608 2004 2752 72,177 9 8 ATÓM 1628 C GLN 237 23.481 11.604 43.483 1,000 15.64 Anisa 1628 C GLN 237 1404 2136 2402 231 -146 2 0 0 ATÓM 1629 ABOUT GLN 237 24.183 12.382 44.164 1,000 18:17 Anisa 1629 ABOUT GLN 237 1581 2508 2817 -227 - 6 - 4 liters 5 ATÓM 1630 CB GLN 237 24.456 11.855 41.217 1,000 17:17 Anisa 1630 CB GLN 237 1912 2080 2532 71 141-7 ATÓM 1631 CG GLN 237 25.304 11.221 40.115 1,000 17.64 Anisa 1631 CG GLN 237 1850 2410 2441 226 95-31 3 ATÓM 1632 CD GLN 237 25.721 12.302 39137 1,000 19.72 Anisa 1632 CD GLN 237 1680 2833 2979 104 317 3 0 7 ATÓM 1633 OE1 GLN 237 26.602 13.110 39.436 1,000 4.27 Anisa 1633 OE1 GLN 237 1841 3145 4234 -213 -187 8 0 9 ATÓM 1634 NE2 GLN 237 24.986 12.399 38.027 1,000 18:53 Anisa 1634 NE2 GLN 237 2007 2298 2735 432 374 2 0 2 ATÓM 1635 N VAL 238 22.221 11.359 43.807 1,000 14.75 Anisa 1635 N VAL 238 1563 1804 2237 -32 -54 4 3 ATÓM 1636 CA VAL 238 21.533 12.075 44862 1,000 14:41 Anisa 1636 CA VAL 238 1535 1553 2388 -44 3 2 ATÓM 1637 C VAL 238 20.861 11.060 45.781 1,000 13:56 Anisa 1637 C VAL 238 1414 1392 2346 82 55 -14 9 ATÓM 1638 ABOUT VAL 238 20.136 10.174 45.302 1,000 15.87 Anisa 1638 ABOUT VAL 238 1655 1639 2737 -218 -285 - 2 2 ATÓM 1639 CB VAL 238 20.467 13.061 44.309 1,000 14.73 Anisa 1639 CB VAL 238 1817 1626 2152 35 -438 - 9 5 ATÓM 1640 CG1 VAL 238 19.805 13.764 45.489 1,000 15.70 Anisa 1640 CG1 VAL 238 1965 1490 2510 174 -524 - 4 2 3 ATÓM 1641 CG2 VAL 238 21.064 13.994 43.280 1,000 16.82 Anisa 1641 CG2 VAL 238 1862 1718 2812 -60 -378 2 2 2 ATÓM 1642 N LYS 239 21.119 11.153 47.071 1,000 14:47 Anisa 1642 N LYS 239 1704 1474 2318 14 -40 1 2 ATÓM 1643 C A LYS 239 20.470 10.360 48.104 1,000 14:43 Anisa 1643 CA LYS 239 1460 1617 2406 106 -168 1 7 9 ATÓM 1644 C LYS 239 19.048 10.852 48.409 1,000 14.82 Anisa 1644 C LYS 239 1533 1456 2642 102 -53 2 3 2 ATÓM 1645 ABOUT LYS 239 18.839 12.067 48 .457 1,000 14.74 Anisa 1645 ABOUT LYS 239 1841 1442 2318 158 -275 1 9 0 ATÓM 1646 CB LYS 239 21.320 10.435 49.385 1,000 16:40 Anisa 1646 CB LYS 239 1995 1712 2527 243 -543 2 5 2 ATÓM 1647 CG LYS 239 20.767 9.549 50498 1. 000 16.65 Anisa 1647 CG LYS 239 1954 1759 2614 -58 -781 2 4 4

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / C.B9SO3S60

ATÓM 164S C Ľ LYS 239 21. 73S 9.511 51683 1 000 1 9. 7 ó Anisa lb4S CD LYS 239 2 954 1820 2732 -1 2 3 3 ó 3 ATÓM 164 9 CE LYS 239 21. 107 8835 52.896 1. 000 2 2.58 Anisa 1649 CE LYS 239 3331 2164 3086 -652 -1502 8 6 3 ATÓM 1650 NZ LYS 239 21.904 8 .883 54.145 1. 000 3.13 Anisa 1650 NZ LYS 239 2817 3360 2612 -471 -943 2 WITH 7 ATÓM 1651 N ALA 240 18.140 9.892 48.659 1. 000 14:35 Anisa 1651 N ALA 240 1429 1607 2418 -156 -334 - 6 1 ATÓM 1652 C A ALA 240 16.791 10.192 49.145 1. 000 13.98 Anisa 1652 C A ALA 240 1468 1635 2210 -151 -335 - 1 0 ATÓM 1653 C ALA 240 16.728 9776 50.505 1. 000 13:44 Anisa 1653 C ALA 240 1439 1388 2279 77 -450 2 2 ATÓM 1654 ABOUT ALA 240 16.514 8.592 50.913 1. 000 16:32 Anisa 1654 ABOUT ALA 240 1932 1567 2699 -215 -673 3 1 4 ATÓM 1655 CB ALA 240 15.712 9565 48.268 1,000 15:21 Anisa 1655 CB ALA 240 1510 1962 2 3 06 -104 -387 - 3 0 7 ATÓM 1656 N PRO 241 16.907 10.701 51.546 1,000 14:23 Anisa 1656 N PRO 241 1634 1551 2221 -87 -292 7 1 ATÓM 1657 C A PRO 241 17.035 10.251 52.940 1,000 14.68 Anisa 1657 CA PRO 241 1718 1681 2180 ’ -350 -174 - 3 0 ATÓM 1658 C PRO 241 15.693 9961 53.5 79 1,000 13.89 Anisa 1658 C PRO 241 1659 1581 2 03 9 -107 -207 - 7 4 ATÓM 1659 ABOUT PRO 241 14.629 10.527 53261 1,000 6.17 Anisa 1659 0 PRO 241 1698 1946 2838 17 -255 1 4 i 6 ATÓM 1660 CB PRO 241 17.689 11.462 53.619 1,000 16.63 Anisa 1660 CB PRO 241 2162 1657 2 50ľ. -460 -487 5 5 ATÓM 1661 CG PRO 241 17.138 12.651 52826 1,000 16:56 Anisa 1661 CG PRO 241 2433 1601 2258 -367 -274 3 1 ATÓM 1662 CD PRO 241 17.164 12.140 51.409 1,000 14.92 Anisa 1662 CD PRO 241 1841 1490 2339 -215 -186 - 6 6 ATÓM 1663 N ARG 242 15.740 9049 54.544 1,000 15.74 Anisa 1663 N ARG 242 1914 1853 2212 -381 -308 2 0 4 ATÓM 1664 CA ARG 242 14.574 8772 55.376 1,000 15:50 Anisa 1664 CA ARG 242 1955 1863 2073 -236 -291 1 8 0 ATÓM 1665 C ARG 242 14.406 9841 56437 1,000 16.60 Anisa 1665 C ARG 242 1889 2011 2 4 07 -120 -411 - 5 1 ATÓM 1666 ABOUT ARG 242 15.372 10.416 56. £ 94 1,000 18:31 Anisa 1666 ABOUT ARG 242 2041 2186 2732 -216 -559 - 18 0 ATÓM 1667 CB ARG 242 14.728 7.419 56.085 1,000 18:38 Anisa 1667 CB ARG 242 2920 1810 2253 -486 -391 2 6 9 ATÓM 1668 CG ARG 242 14.564 6273 55094 1,000 18:42 Anisa 1668 CG ARG 242 2372 1873 2755 -88 162 - 15 5 ATÓM 1669 CD ARG 242 14.854 4935 55.796 1,000 2 3.07 Anisa 1669 CD ARG 242 3380 2022 3366 470 -483 - 2 17 ATÓM 1670 NE ARG 242 16.334 4954 55.991 1,000 6.69 Anisa 1670 NE ARG 242 3498 2727 3916 444 -829 4 7 1 ATÓM 1671 CZ ARG 242 16.941 3921 56584 1,000 2 7.19 Anisa 1671 CZ ARG 242 3166 2879 4284 -297 -1143 8 0 2 ATÓM 1672 NH1 ARG 242 16.157 2,913 56.989 1,000 3.14 Anisa 1672 NH1 ARG 242 3810 3235 5546 -316 528 7 2 6 ATÓM 1673 NH2 ARG 242 18.241 3.889 56.779 1,000 3 1.13 Anisa 1673 NH2 ARG 242 3043 2925 5859 227 -769 4 8 4 ATÓM 1674 N HIS 243 13.188 10.057 56872 1,000 17:55 Anisa 1674 N HIS 243 1979 2233 2457 -165 -173 - 7 4 ATÓM 1675 CA HIS 243 12.913 11.050 57914 1,000 17.84 Anisa 1675 C A HIS 243 2186 2139 2452 -260 -123 - 7 5 ATÓM 1676 C HIS 243 11.644 10.627 58.643 1,000 17:52 Anisa 1676 C HIS 243 2102 2084 2470 -248 -164 - 3 2 5 ATÓM 1677 ABOUT HIS 243 10.870 9803 58132 1,000 2 0.23 Anisa 1677 ABOUT HIS 243 2226 2593 2868 -551 -3 23 - 3 9 2 Z \ TOM 1678 CB HIS 243 12.865 12.456 57.324 1,000 19.74

SUBSTffiE SHEET (RULE 26)

WO 99/33994

PCT / GB08OJ860

Anisa 1678 CB HIS 243 2770 2248 2482 -188 - 10 ó 8 j ATÓM 1679 CG HIS 243 11.922 12.630 56.187 1,000 2'2 * Anisa 1679 CG HIS 243 344 9 2513 2624 164 -382 0 ATÓM 1680 ND1 HIS 243 12. 209 12.299 54 .879 I '. 000 2 5.87 Anisa 1680 ND1 HIS 243 4780 2575 2473 -609 -403 5 3 ATÓM 1681 CD2 HIS 243 10.633 13.034 56172 1,000 2 9.11 Anisa 1681 CD2 HIS 243 3220 4490 3348 121 -421 1630 ATÓM 1682 CE1 HIS 243 11.182 12.573 54.109 1,000 3 2.92 Anisa 1682 CE1 HIS 243 5835 3672 3001 -1102 -1367 589 ATÓM 1683 NE2 HIS 243 10.214 13.012 54.875 1,000 6.95 Anisa 1683 NE2 HIS 243 5719 4201 4119 1019 -2016 987 ATÓM 1684 N HIS 244 11.437 11.194 59831 1,000 18.87 Anisa 1684 N HIS 244 2523 2477 2171 -88 -141-1 17 ATÓM 1685 CA HIS 244 10.302 10.801 60649 1,000 2 0.83 Anisa 1685 CA HIS 244 2802 2485 2628 171 251 272 ATÓM 1686 C HIS 244 9.927 11.968 61551 1,000 2 0.33 Anisa 1686 C HIS 244 1803 2969 2953 -31 - 78 - 2 7 3 ATÓM 1687 0 HIS 244 10.482 13.073 61510 1,000 2 1.71 Anisa 1687 0 HIS 244 2057 3418 2774 -535 145-8 5 3 ATÓM 1688 CB HIS 244 10.714 9557 61.468 1,000 4.38 Anisa 1688 CB HIS 244 4066 2644 2553 -76 -390 441 ATÓM 1689 CG HIS 244 11.859 9725 62423 1,000 8.34 Anisa 1689 CG HIS 244 4158 3498 3113 696 -727-8 9 ATÓM 1690 ND1 HIS 244 13.132 9205 62268 1,000 3 2.35 Anisa 1690 ND1 HIS 244 4012 4471 3808 548 -485-8 5 0 ATÓM 1691 CD2 HIS 244 11.928 10391 63609 1,000 5.21 Anisa 1691 CD2 HIS 244 2937 4137 2505 -373 44 2 1 9 ATÓM 1692 CE1 HIS 244 13.887 9531 63312 1,000 3 1.71 Anisa 1692 CE1 HIS 244 4157 4277 3613 1224 -749-5 5 1 8 ATÓM 1693 NE2 HIS 244 13,146 10.263 64150 1,000 4.52 Anisa 1693 NE2 HIS 244 3165 3517 2633 94 -82,492 ATÓM 1694 N VAL 245 8.890 11.687 62349 1,000 2 3.87 Anisa 1694 N VAL 245 2627 3119 3322 -251 531-310 ATÓM 1695 CA VAL 245 8.473 12.691 63349 1,000 4.85 Anisa 1695 CA VAL 245 2785 3770 2888 481 149-2 9 3 ATÓM 1696 C VAL 245 8624 12.079 64735 1,000 2 6.03 Anisa 1696 C VAL 245 3220 3558 3112 -289 180 8 9 ATÓM 1697 0 VAL 245 8023 11.025 64969 1,000 7.98 Anisa 1697 0 VAL 245 3120 3085 4428 42 295-5 9 ATÓM 1698 CB VAL 245 7.020 13.114 63099 1,000 2 6.02 Anisa 1698 CB VAL 245 2621 3489 3777 94 - 103 - 5 6 9 ATÓM 1699 CG1 VAL 245 6586 14.114 64161 1,000 2 8.06 Anisa 1699 CG1 VAL 245 2717 3330 4614 159 745 - 4 8 5 ATÓM 1700 CG2 VAL 245 6,927 13.705 61680 1,000 3 0.51 Anisa 1700 CG2 VAL 245 3564 3809 4220 1264 -305 3 3 ATÓM 1701 N ALA 246 9.399 12.696 65603 1,000 2 8.08 Anisa 1701 N ALA 246 4338 3787 2543 -850 250 254 ATÓM 1702 CA ALA 246 9567 12.316 67003 1,000 7.45 Anisa 1702 CA ALA 246 4363 3360 2707 292 275 373 ATÓM 1703 C ALA 246 8356 12.740 67833 1,000 3 2.68 Anisa 1703 C ALA 246 4915 4473 3031 98,880 197 ATÓM 1704 0 ALA 246 7.774 13.791 67563 1,000 9.54 Anisa 1704 0 ALA 246 3522 4283 3417 -224 876 - 3 2 9 ATÓM 1705 CB ALA 246 10.819 13.010 67542 1,000 3 0.33 Anisa 1705 CB ALA 246 4564 3949 3011 615 -221 - 4 2 ATÓM 1706 N ALA 247 8048 11.958 68849 1,000 3 4.09 Anisa 1706 N ALA 247 4483 5156 3311 -1190 466 393 ATÓM 1707 CA ALA 247 7.036 12.190 69859 1,000 4.23 Anisa 1707 CA ALA 247 4188 5627 3189 -1215 315 515 ATÓM 1708 C ALA 247 7609 12.910 71081 1. 000 3 3.31 Anisa 1708 C ALA 247 5419 4684 2555 249 -506 1147

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PC1 / GB98 / 03860

ATÓM 1,709 0 ALA 24 7 8733 12.708 7]. 523 1.000 Anisa 1709 0 ALA 247 5787 4478 4 2 5 9 -378 ATÓM 1710 CB ALA 247 6.383 10.881 70314 1. 000 Anisa 1710 CB ALA 247 8374 Ó726 2801 -'2800 ATÓM 1711 N PRO 248 6.817 13.851 71 577 1,000 Anisa 1711 N PRO 248 5771 5458 4836 -300 ATÓM 1712 C A PRO 248 7256 14.581 72773 1,000 Anisa 1712 C A PRO 248 7568 5478 3996 - 64 5 ATÓM 1713 C PRO 248 7. 161 13.618 73948 1,000 Anisa 1713 C PRO 248 7978 5660 5075 -1,446 ATÓM 1714 0 PRO 248 6.251 12.794 74014 1,000 Anisa 1714 0 PRO 248 7651 5391 4237 -1127 ATÓM 1715 CB PRO 248 6196 15.674 72897 1,000 Anisa 1715 CB PRO 248 8563 4816 5523 -513 ATÓM 1716 CG PRO 248 4973 15.053 72299 1,000 Anisa 1716 CG PRO 248 7228 5564 6545 -108 ATÓM 1717 CD PRO 248 5489 14.272 71114 1,000 Anisa 1717 CD PRO 248 6395 4579 6006 937 ATÓM 1718 N ARG 249 8.109 13.683 74883 1,000 Anisa 1718 N ARG 249 9141 6341 3 04 5 -1317 ATÓM 1719 CA ARG 249 7865 12.783 76024 1,000 Anisa 1719 CA ARG 249 10023 6914 415 6 -1098 ATÓM 1720 C ARG 249 6.844 13.466 76916 1,000 Anisa 1720 C ARG 249 5561 8382 3568 -2484 ATÓM 1721 0 ARG 249 6.244 12.915 77831 1,000 Anisa 1721 0 ARG 249 7572 6368 7 43 3 -377 ATÓM 1722 CB ARG 249 9.177 12.459 76721 1,000 Anisa 1722 CB ARG 249 8950 7715 4 32 6 705 ATÓM 1723 CG ARG 249 9915 11.278 76110 1,000 Anisa 1723 CG ARG 249 12881 7330 6779 1135 ATÓM 1724 CD ARG 249 10.403 10.303 77165 1,000 Anisa 1724 CD ARG 249 11721 7991 7984 2171 ATÓM 1725 NE ARG 249 11.124 9.162 76.580 1,000 Anisa 1725 NE ARG 249 8627 9977 8271 2362 ATÓM 1726 CZ ARG 249 12.039 8493 77282 1,000 Anisa 1726 CZ ARG 249 10269 9417 7942 2304 ATÓM 1727 NH1 ARG 249 12.297 8.893 78521 1,000 Anisa 1727 NH1 ARG 249 22286 6161 5559 2015 ATÓM 1728 NH2 ARG 249 12.682 7462 76761 1,000 Anisa 1728 NH2 ARG 249 5358 10062 10295 1004 ATÓM 1729 N ALA 254 1.981 18.918 75430 1,000 Anisa 1729 N ALA 254 15501 7922 8964 -4,581 ATÓM 1730 CA ALA 254 2.287 20.081 76257 1,000 Anisa 1730 CA ALA 254 12510 8110 8286 -3,993 ATÓM 1731 C ALA 254 2.943 21216 75489 1,000 Anisa 1731 C ALA 254 8383 5719 9040 -506 ATÓM 1732 0 ALA 254 4.174 21.309 75487 1,000 Anisa 1732 0 ALA 254 8056 8109 11332 1602 ATÓM 1733 CB ALA 254 3264 19.667 77351 1,000 Anisa 1733 CB ALA 254 12589 7262 3131 -866 ATÓM 1734 N GLY 255 2,200 22.108 74846 1,000 Anisa 1734 N GLY 255 8029 5451 7190 594 ATÓM 1735 CA GLY 255 2.880 23.171 74098 1,000 Anisa 1735 CA GLY 255 5181 4570 5465 1424 ATÓM 1736 C GLY 255 3,640 22.565 72921 1,000 Anisa 1736 C GLY 255 4227 4772 5749 557 ATÓM 1737 0 GLY 255 4. 580 23.163 72398 1,000 Anisa 1737 0 GLY 255 2978 6491 5715 -128 ATÓM 1738 N SER 256 3. 164 21.387 72509 1,000 AÍJISOU 1738 N SER 256 5047 4594 4 52 7 389 ATÓM 1739 CA SER 256 3.738 20.606 71.429 1. 000

8.23

1-5 J 9 11 3 0

7.11 1464,685 4 2.28

933-9 7

4.85 1412 214

9.25

552 985

5.48 2574 - 7 9 6

9.74 1238 - 1 3 8

0.89 2210 -1064 4 4.69

954 - 5 7 7

8.75 1069 - 4 7 7

5:51

895 566

6.09 -7 12 3 7

6.25. 1799 3 9 9 5

5.24 2864 1 2 7 0 7 1.04 3707 6 2 2

2.89 2723 409

0.73 2650 - 2 6 6 72.71 2152 133

9.50 1622 3 8 7 4 67.68 3885 221

5.24

-1437 2 3 4 7 7 6.08 1617 15 9 2 60.91 2886 1 3 1 2 7 2.37 4553 3 3 8 1

0.48 4570 - 1 1 1 2 5 4.40 2922 - 9 4 0 4 0.05

836-9 2 1

8.81 702 - 1 5 6 1

9.96

-136 - 2226 3 7.29 11-8 5 3

5.71

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98O3860

Anisa 1739 C Ä SER 256 4737 4 53 3 4299 560 - 5 C 1-9 1 9 ATÓM 1740 C SER 256 2,983 20.742 70118 1. 000 r *> 9 3 Anisa 1740 C SER 256 4584 4669 4019 -98 -85 9 1 ATÓM 1741 ABOUT SER 256 3251 20,000 69162 ľ.000 3 3.92 Anisa 1741 ABOUT SER 256 3575 6107 3207 503 304 377 ATÓM 1742 CB SER 256 3845 19.136 71853 1,000 3 0.17 Anisa 1742 CB SER 256 3125 4830 3509 624 212-4 4 2 ATÓM 1743 OG SER 256 2,688 18.752 72601 1,000 6 1.15 Anisa 1743 OG SER 256 2987 8497 11750 451 1943 2 6 4 0 ATÓM 1744 N SER 257 2.065 21.700 70030 1,000 5.54 Anisa 1744 N SER 257 4037 5989 3479 347 242-8 6 ATÓM 1745 CA SER 257 1,379 21.993 68767 1,000 3 0.95 Anisa 1745 CA SER 257 2824 5827 3109 170 672 - 5 0 8 ATÓM 1746 C SER 257 2378 22.538 67760 1,000 3 0.63 Anisa 1746 C SER 257 3181 5524 2934 -476 764 - 1 2 9 6 ATÓM 1747 ABOUT SER 257 3.359 23.159 68199 1,000 3 4.70 Anisa 1747 ABOUT SER 257 3500 6070 3616 -829 603 - 1 5 1 7 ATÓM 1748 CB SER 257 0331 23.088 69.036 1,000 8.70 Anisa 1748 CB SER 257 3085 6518 5103 796 1381 435 ATÓM 1749 OG SER 257 0801 24.361 68601 1,000 6 5.12 Anisa 1749 OG SER 257 8002 5175 11565 -999 -3375 383 ATÓM 1750 N ARG 258 2,119 22.384 66471 1,000 3 0.51 Anisa 1750 N ARG 258 3668 5068 2855 -332 677-9 9 5 ATÓM 1751 CA ARG 258 2.997 22.819 65396 1,000 8.15 Anisa 1751 CA ARG 258 3100 4620 2976 -106 358-5 5 4 4 ATÓM 1752 C ARG 258 2,198 22.913 64096 1,000 2 5.64 Anisa 1752 C ARG 258 3488 3381 2872 -676 273-9 0 4 ATÓM 1753 ABOUT ARG 258 1.132 22294 63.981 1,000 2 4.93 Anisa 1753 ABOUT ARG 258 3162 3240 3070 -441 477 - 5 6 0 ATÓM 1754 CB ARG 258 4.175 21.873 65154 1,000 27.21 Anisa 1754 CB ARG 258 3158 4041 3141 -446 313 -1352 ATÓM 1755 CG ARG 258 3861 20.508 64.570 1,000 3 0.90 Anisa 1755 CG ARG 258 4782 3429 3531 -737 -738- 3 8 9 ATÓM 1756 CD ARG 258 5.039 19.537 64769 1,000 6.65 Anisa 1756 CD ARG 258 5937 3466 4523 106 477 306 ATÓM 1757 NE ARG 258 4597 18.176 64411 1,000 32.42 Anisa 1757 NE ARG 258 3372 3858 5089 -85 -274 528 ATÓM 1758 CZ ARG 258 4633 17.777 63143 1,000 7.32 Anisa 1758 CZ ARG 258 5670 2958 5553 155 680 4 3 ATÓM 1759 NH1 ARG 258 5.075 18.622 62217 1,000 9.98 Anisa 1759 NH1 ARG 258 3077 3435 4881 -150 -211 - 1 0 0 ATÓM 1760 NH2 ARG 258 4.210 16.566 62824 1,000 8.66 Anisa 1760 NH2 ARG 258 5812 3151 5724 -190 -1632 865 ATÓM 1761 N THR 259 2806 23.572 63.120 1,000 2 3.62 Anisa 1761 N THR 259 2625 3578 2771 -519 315 -1037 ATÓM 1762 CA THR 259 2,337 23.482 61730 1,000 2 1.97 Anisa 1762 CA THR 259 2614 2934 2800 -36 247 - 1 0 4 0 ATÓM 1763 C THR 259 3.528 23.197 60808 1,000 19.76 Anisa 1763 C THR 259 2257 2663 2587 -38 21-6 9 9 ATÓM 1764 ABOUT THR 259 4.698 23.411 61159 1,000 2 1.13 Anisa 1764 ABOUT THR 259 2464 3096 2468 -495 -10 - 2 8 7 ATÓM 1765 CB THR 259 1,682 24.793 61278 1,000 2 4.04 Anisa 1765 CB THR 259 2125 3084 3927 -157 - 1 2 2 9 ATÓM 1766 OG1 THR 259 2,697 25.790 61041 1,000 3.14 Anisa 1766 OG1 THR 259 2297 2848 3648 196 -142-8 2 9 ATÓM 1767 CG2 THR 259 0.760 25.408 62.331 1. 000 5.17 Anisa 1767 CG2 THR 259 2941 3229 3393 726 264-1 ATÓM 1768 N SER 260 3 .234 22.706 59.600 1,000 2 0.41 Anisa 1768 N SER 260 2386 2762 2609 -61 74 - 8 0 7 ATÓM 1769 C A SER 260 4,225 22515 58551 1,000 19:33 Anisa 1769 CA SER 260 2488 2459 2399 192 8 - 3 3 4

SUBSTTTUTE SHEET (RULE 26) on 99/33994

PCT / GB9S / 03860

ATÓM 1770 C SER 260 3.587 Anisa 1770 C SER 260 1996 ATÓM 1771 ABOUT SER 260 2.375 Anisa 1771 ABOUT SER 260 1917 ATÓM 1772 CB SER 260 4. 73S Anisa 1772 CB SER 260 2491 ATÓM 1773 OG SER 260 3656 Anisa 1773 OG SER 260 2758 ATÓM 1774 N SER 261 4 .474 Anisa 1774 N SER 261 2189 ATÓM 1775 C A SER 261 4.148 Anisa 1775 CA SER 261 2074 ATÓM 1776 C SER 261 5066 Anisa 1776 C SER 261 1720 ATÓM 1777 ABOUT SER 261 6.272 Anisa 1777 ABOUT SER 261 1712 ATÓM 1778 CB SER 261 4471 Anisa 1778 CB SER 261 2903 ATÓM 1779 OG SER 261 4404 Anisa 1779 OG SER 261 5435 ATÓM 1780 N VAL 262 4467 Anisa 1780 N VAL 262 1751 ATÓM 1781 CA VAL 262 5247 Anisa 1781 CA VAL 262 1871 ATÓM 1782 C VAL 262 4914 Anisa 1782 C VAL 262 1460 ATÓM 1783 ABOUT VAL 262 3759 Anisa 1783 □ VAL 262 1488 ATÓM 1784 CB VAL 262 4.902 Anisa 1784 CB VAL 262 2144 ATÓM 1785 CG1 VAL 262 5.567 Anisa 1785 CG1 VAL 262 2433 ATÓM 1786 CG2 VAL 262 5.335 Anisa 1786 CG2 VAL 262 2390 ATÓM 1787 N PHE 263 5894 Anisa 1787 N PHE 263 1497 ATÓM 1788 CA PHE 263 5762 Anisa 1788 CA PHE 263 1654 ATÓM 1789 C PHE 263 6479 Anisa 1789 C PHE 263 1432 ATÓM 1790 ABOUT PHE 263 7.732 Anisa 1790 ABOUT PHE 263 1415 ATÓM 1791 CB PHE 263 6.364 Anisa 1791 CB PHE 263 1658 ATÓM 1792 .CG PHE 263 6062 Anisa 1792 CG PHE 263 1616 ATÓM 1793 CD1 PHE 263 6,750 Anisa 1793 CD1 PHE 263 1977 ATÓM 1794 CD2 PHE 263 5.005 Anisa 1794 CD2 PHE 263 1549 ATÓM 1795 CE1 PHE 263 6.468 Anisa 1795 CE1 PHE 263 1721 ATÓM 1796 CE2 PHE 263 4703 Anisa 1796 CE2 PHE 263 1482 ATÓM 1797 CZ PHE 263 5383 Anisa 1797 CZ PHE 263 1935 ATÓM 1798 N PHE 264 5721 Anisa 1798 N PHE 264 1277 ATÓM 1799 C A PHE 264 6267 Anisa 1799 CA PHE 264 1177 ATÓM 1800 C PHE 264 6,440

22.871 57.210 I. 000 1 S. 7 8 2 544 259 5 -379 -311 22.758 56988 1. 000 2 1. 2 0 2448 3689 -75 -269 - 5 7 4 21.076 58.480 1. 000 2 0. 2 8 2458 2755 160 101 4 5 20.197 58.227 1,000 2 2. 7 0 2574 3294 -113 -284 - 1 6 9 23.329 56.330 1,000 1 8. 7 9 2215 2737 -55 -92 3 5 23. 585 54.929 1,000 1 6. 8 8 1718 2622 22 -117 - 404 22.672 54106 1,000 1 7. 2 5 1833 3000 101 -350 - 4 9 1 22.876 54173 1,000 1 9. 9 6 2417 3456 50 -483 - • 781 25.028 54.503 1,000 1 9. 9 5 1675 3002 164 -112 1-13 5 25.127 53107 1,000 3 5. 6 4 4814 3293 -1089 -767 1 2 6 3 21.722 53.435 1,000 1 5. 5 6 2021 2140 -75 -40 - 3 4 6 20.713 52.711 1,000 1 5. 4 1 1938 204B 43 21 -19 6 20.874 51..242 1,000 1 4. 05 1784 2095 -13 29 - 14 4 20.712 50.344 1,000 15 Dec 4 5 1900 248 L -175 -94 -19 1 19.307 53.253 1,000 1 6. 8 7 2005 2260 165 -164 2 3 18.275 52.364 1,000 2 0. 0 1 2006 3165 4 -191 - 637 19.200 54.715 1,000 1 8. 6 3 2242 2446 147 -397 175 21.163 50.412 1,000 1 3. 7 3 1573 214 8 5 -64 1 7 6 21.411 48.994 1,000 1 3. 04 1196 2105 -12 -193 113 20.253 48.284 1,000 1 3. 5 6 1351 2370 -175 -98 - 8 7 20.177 48281 1,000 1 3. 8 3 1437 2403 -82 -299 - 1 0 0 22.770 48594 1,000 1 3. 5 0 1374 2098 -295 -97 3 4 23.148 47.135 1,000 13. 3 4 1358 2 096 -159 -111 8 2 22.635 46.051 1,000 1 4. 9 5 1547 2156 -354 -131 - 3 8 24.048 46.883 1,000 1 5. 3 7 1557 2735 -139 -264 303 22.945 44.720 1,000 1 4. 5 8 1621 2196 -242 71 -14 4 24366 45566 1,000 1 4. 7 1 1428 2680 -20 -261 137 23.809 44.479 1,000 1 6. 5 5 1492 2862 -152 29: L 4 19.405 47.588 1,000 1 2. 0 7 1343 19 6? -66 -49 1 9 18. 328 46.769 1,000 1 1. 9 0 1289 2 05 clay - 129 34 - 2 1 18.775 45.314 1,000 1 1. 7 6

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT7GB98'03860

Anisa 1S00 C PHE 264 1206 1258 2004 -121 -42 S ATÓM 1801 ABOUT PHE 264 5418 19.097 44.683 1. 000 L2, .5 5 Anisa 1801 ABOUT PHE 264 1165 1473 2133 -77 -120 4 ó ATÓM 1802 CB PHE 264 5.346 17.099 46.773 1,000 12:39 Anisa 1802 CB PHE 264 1101 1498 2110 -304 -42 6 3 ATÓM 1803 CG PHE 264 5022 16.558 48.150 1,000 13.97 Anisa 1803 CG PHE 264 1647 1465 2197 -290 13 12 1 ATÓM 1804 CD1 PHE 264 5.960 15.848 48.852 1,000 7.17 Anisa 1804 CD1 PHE 264 2039 1976 2471 -422 -410 497 ATÓM 1805 CD2 PHE 264 3747 16.679 48668 1,000 17:41 Anisa 1805 CD2 PHE 264 1835 2359 2419 -440 433 112 ATÓM 1806 CE1 PHE 264 5661 15.247 50.053 1,000 2 0.59 Anisa 1806 CE1 PHE 264 2616 2710 2496 -556 -425 725 ATÓM 1807 CE2 PHE 264 3458 16,133 49.906 1,000 2.51 Anisa 1807 CE2 PHE 264 2151 4047 2355 -787 106 553 ATÓM 1808 CZ PHE 264 4386 15.350 50562 1,000 2 0.88 Anisa 1808 CZ PHE 264 2889 2376 2669 -936 -22 306 ATÓM 1809 N LEU 265 7.676 18.756 44811 1,000 11.81 Anisa 1809 N LEU 265 1192 1248 2047 ' -37 47 1 9 ATÓM 1810 CA LEU 265 7.900 19.000 43.374 1,000 1.12 Anisa 1810 CA LEU 265 1264 1269 2028 -223 16-63 ATÓM 1811 C LEU 265 7915 17.617 42.703 1,000 12:10 Anisa 1811 C LEU 265 1266 1298 2033 -117 -81 3 ATÓM 1812 ABOUT LEU 265 8.842 16.834 42.915 1,000 12.93 Anisa 1812 ABOUT LEU 265 1367 1283 2260 -107 -153 4 4 ATÓM 1813 CB LEU 265 9246 19.730 43.156 1,000 12:59 Anisa 1813 CB LEU 265 1399 1364 2019 -257 57-9 ATÓM 1814 CG LEU 265 9,500 20.124 41.709 1,000 12:19 Anisa 1814 CG LEU 265 1168 1399 2066 -292 -248 302 ATÓM 1815 CD1 LEU 265 8.620 21.314 41.318 1,000 13:29 Anisa 1815 CD1 LEU 265 1518 1546 1984 84 36 1 9 ATÓM 1816 CD2 LEU 265 10.971 20.458 41.449 1,000 13:14 Anisa 1816 CD2 LEU 265 1204 1593 2197 -234 41-20 ATÓM 1817 N ARG 266 6842 17.249 41.996 1,000 6.12 Anisa 1817 N ARG 266 1412 1127 2043 -220 -191 4 5 ATÓM 1818 CA ARG 266 6586 15913 41.488 1,000 7.12 Anisa 1818 CA ARG 266 1372 1201 2012 -258 0 8 0 ATÓM 1819 C ARG 266 6619 15.965 39972 1,000 11.75 Anisa 1819 C ARG 266 1203 1315 1948 29 -267 ATÓM 1820 ABOUT ARG 266 6.032 16.860 39.396 1,000 13.6 Anisa 1820 ABOUT ARG 266 1430 1318 2214 5 -173,281 ATÓM 1821 CB ARG 266 5.243 15.370 41.994 1,000 12.95 Anisa 1821 CB ARG 266 1142 1477 2302 -189 43-33 ATÓM 1822 CG ARG 266 5.036 15.606 43.488 1,000 13.80 Anisa 1822 CG ARG 266 1351 1686 2207 -159 66 - 115 ATÓM 1823 CD ARG 266 3723 15.041 43.993 1,000 12.70 Anisa 1823 CD ARG 266 1369 1362 2094 67 -22 8 4 ATÓM 1824 NE ARG 266 2.581 15.648 43.281 1,000 12.97 Anisa 1824 NE ARG 266 1343 1155 2428 52 -165 - 1 3 7 ATÓM 1825 CZ ARG 266 1.304 15.281 43.500 1,000 11:34 Anisa 1825 CZ ARG 266 1432 1009 1869 46 -149 - 1 0 3 ATÓM 1826 NH1 ARG 266 0.995 14.414 44.476 1,000 13:39 Anisa 1826 NH1 ARG 266 1802 1165 2119 -11 -38 7 2 ATÓM 1827 NH2 ARG 266 0305 15.821 42826 1,000 12:55 Anisa 1827 NH2 ARG 266 1490 1067 2210 125 -357-1 1 5 9 ATÓM 1828 N PRO 267 7.237 14.951 39357 1,000 12.74 Anisa 1828 N PRO 267 1418 1394 2030 16 -146 108 ATÓM 1829 CA PRO 267 7298 14.947 37.887 1,000 13.88 Anisa 1829 CA PRO 267 1442 1786 2047 167 -125-8 4 ATÓM 1830 C PRO 267 5957 14.722 37.222 1,000 12.61 Anisa 1830 C PRO 267 1413 1508 1868 -6 44 2 7

SUBSTfTUTE SHEET (RULE 26)

WO 09 3.1094

PCT / GBOS'03860

ATÓM 1831 0 PRO 2 é 7 4. 9 9 S Anisa 1S 3 1 0 PRO 2 6 7 1648 ATÓM 1832 CB PRO 2 67 8233 Anisa 1832 CB PRO 267 1435 ATÓM 1833 CG PRO 267 8.033 Anisa 1833 CG PRO 267 1885 ATÓM 1834 CD PRO 267 7.872 Anisa 1834 CD PRO 267 1803 ATÓM 1835 N ASN 268 5.933 Anisa 1835 N ASN 268 1601 ATÓM 1836 C A ASN 268 4. 800 Anisa 1836 C A ASN 268 1793 ATÓM 1837 C ASN 268 4. 723 Anisa 1837 C ASN 268 1485 ATÓM 1838 0 ASN 268 5,702 Anisa 1838 0 ASN 268 1698 ATÓM 1839 CB ASN 268 4. 997 Anisa 1839 CB ASN 268 2597 ATÓM 1840 CG ASN 268 5.011 Anisa 1840 CG ASN 268 2255 ATÓM 1841 ODL ASN 268 4069 Anisa 1841 ODL ASN 268 2573 ATÓM 1842 ND2 ASN 268 6066 Anisa 1842 ND2 ASN 268 2408 ATÓM 1843 N ALA 269 3531 Anisa 1843 N ALA 269 1677 ATÓM 1844 CA ALA 269 3.278 Anisa 1844 CA ALA 269 1459 ATÓM 1845 C ALA 269 4182 Anisa 1845 C ALA 269 1289 ATÓM 1846 0 ALA 269 4581 Anisa 1846 0 ALA 269 1718 ATÓM 1847 CB ALA 269 1.806 Anisa 1847 CB ALA 269 1300 ATÓM 1848 N ASP 270 4482 Anisa 1848 N ASP 270 1688 ATÓM 1849 CA ASP 270 5247 Anisa 1849 CA ASP 270 1747 ATÓM 1850 C ASP 270 6749 Anisa 1850 C ASP 270 1714 ATÓM 1851 0 ASP 270 7483 Anisa 1851 0 ASP 270 1952 ATÓM 1852 CB ASP 270 4718 Anisa 1852 CB ASP 270 2461 ATÓM 1853 CG ASP 270 4968 Anisa 1853 CG ASP 270 2284 ATÓM 1854 ODL ASP 270 5.386 Anisa 1854 ODL ASP 270 3424 ATÓM 1855 OD2 ASP 270 4646 Anisa 1855 OD2 ASP 270 3317 ATÓM 1856 N PHE 271 7221 Anisa 1856 N PHE 271 1556 ATÓM 1857 CA PHE 271 8671 Anisa 1857 CA PHE 271 1624 ATÓM 1858 C PHE 271 9.275 Anisa 1858 C PHE 271 1402 ATÓM 1859 0 PHE 271 8.790 Anisa 1859 0 PHE 271 1900 ATÓM 1860 CB PHE 271 8. 942 Anisa 1860 CB PHE 271 1700 ATÓM 1861 CG PHE 271 10.386

14.155 37.772 1. 000 1 3. No 0 1355 2164 -160 41S, 9 3 13.761 37599 1,000 15:30 1740 2637 115 -28 - 16 9 12.846 38.764 1,000 15.82 1804 23 24 381 -270 - 19 7 13.746 39.965 1,000 14.73 1356 24 3 8 311 - 6 ó 6 - 2 0 5 15.051 35939 1,000 13:27 1665 17 77 -126 -43 - 12 7 14.709 35.073 1,000 1 3. 7 2 1401 2018 -214 -236 - 7 1 13.192 34.875 1,000 13:14 1350 215 6 -213 104 5 4 12.467 34. 934 1,000 13.90 1416 2167 -91 123 - 3 6 15.338 33.690 1,000 15.74 1369 2016 -66 -437 1 3 5 16.862 33. 811 1,000 15:41 1439 2162 -17 -184 4 7 17.454 34 352 1,000 17.75 1686 2487 42 91 -98 17.503 33.319 1,000 16.61 1355 2 54 6 -50 -57 1 4 2 12.712 34594 1,000 13.99 1467 217 2 -356 -65 1 7 0 11.286 34.353 1,000 13:42 1405 2234 -208 -118 1 0 7 10.729 33.252 1,000 13.93 1538 2466 -168 -515: 3 9.550 33.318 1,000 14.97 1476 2494 -143 112 8 6 11.051 34.008 1,000 13.76 1474 2454 -60 -61 1 2 3 11.541 32.251 1,000 14:38 1476 2300 -151 30-5 11.079 31.098 1,000 14.83 1693 21S4 -99 -42 6 8 11.287 31.227 1,000 15.68 1886 2357 -224 143 8 6 11.008 30.255 1,000 17:12 2354 22C0 -80 139 2 2 6 11.681 29.800 1,000 17.67 1966 2288 -75 -319 1 2 6 13.168 29.649 1,000 18:22 2024 2613 -88 -80 4 7 4 13.826 30.607 1,000 2 0.55 1541 2844 -47 -287 4 2 5 13.698 28.552 1,000 2 3.06 2727 2719 -49 -136 8 1 2 11.668 32.413 1,000 13.93 1318 2417 97 31 4 1 11.723 32.644 1,000 14:41 1430 2423 110 29 2 6 3 10.349 32.325 1,000 13:31 1430 2225 -30 28 2 1 8 9.340 32.870 1,000 14.91 1374 2392 -26 240 1 9 2 12.146 34098 1,000 15:57 1721 2495 -66 -36 9 11.791 34 .516 1,000 14:56

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / G B 98/03860

- 75 ANISOU ATOM ANISOU ATOM ANISOU ATOM ANISOU ATOM ANISOU ATOM ANISOU ATOM ANISOU

1861 CG PHE 1862 CD1 PHE 1862 CD1 PHE 1863 CD2 PHE 1863 CD2 PHE 1864 CE1 PHE 1864 CE1 PHE 1865 CE2 PHE 1865 CE2 PHE 1866 CZ PHE 1866 CZ PHE 1867 N THR 1867 N THR 1868 CA THR 1868 CA THR 1869 C THR 1869 C THR 1870 ABOUT THR 1870 ABOUT THR 1871 CB THR 1871 CB THR 1872 OG1 THR 1872 OG1 THR 1873 CG2 THR 1873 CG2 THR 1874 N PHE 1874 N PHE 1875 CA PHE 1875 CA PHE 1876 C PHE 1876 C PHE 1877 ABOUT PHE 1877 ABOUT PHE 1878 CB PHE 1878 CB PHE 1879 CG PHE 1879 CG PHE 1880 CD1 PHE 1880 CD1 PHE 1881 CD2 PHE 1881 CD2 PHE 1882 CE1 PHE 1882 CE1 PHE 1883 CE2 PHE 1883 CE2 PHE 1884 CZ PHE 1884 CZ PHE 1885 N SER 1885 N SER 1886 CA SER 1886 CA SER 1887 C SER 1887 C SER 1888 ABOUT SER 1888 0 SER 1889 CB SER 1889 CB SER 1890 OG SER 1890 OG SER 1891 N VAL 1891 N VAL

271 1729 1320 2485 - 152 33 - 1 2 4 271 11. 4Ó0 12 .369 33.814 1,000 ¾ * 7 - »7 6 271 1714 1581 3452 -235 392 - 2 4 9 271 10.698 10.972 35.570 i: 000 4.18 271 2182 1543 3130 -95 -540 172 271 12.780 12.092 34. 166 1,000 17:54 271 1838 1700 3128 -291 113 - 5 0 271 11. 997 10.609 35.899 1,000 18.84 271 1935 1646 3578 -392 -396 425 271 13.039 11.154 35.162 1,000 17:25 271 2444 1697 2415 -486 -19- 3 9 4 272 10.278 10.298 31.453 1,000 13.78 272 1514 1641 2083 30 19 15 4 272 10,811 9046 30.938 1,000 13.99 272 1551 1660 2105 -99 83 6 7 272 12.246 8841 31.410 1,000 14.71 272 1598 1549 2441 -3 108 357 272 13.046 9808 31.424 1,000 16:23 272 1646 1742 2780 -246 5 18 5 272 10.751 9.117 29.388 1,000 16:27 272 1856 2205 2119 191 125 8 272 9.341 9221 29.032 1,000 17.99 272 1996 2473 2368 64 -190 264 272 11.249 7.856 28.723 1,000 17.94 272 2423 2167 2227 173 177-9 4 273 12.567 7,600 31.743 1,000 14.91 273 1644 1521 2499 92,238 218 273 13.894 7,253 32.254 1,000 15:16 273 1602 1813 2345 296 277 5 5 273 14.350 5.899 31724 1,000 14.69 273 1408 1647 2528 24,479 1 7 8 273 13541 5086 31262 1,000 15.91 273 1738 1767 2541 -115 450 119 273 13.899 7.301 33.769 1,000 15.77 273 1758 1921 2314 -344 286 123 273 12.931 6336 34424 1,000 14:54 273 1390 1726 2410 -95 -11 195 273 11.601 6743 34.655 1,000 16.64 273 1457 2343 2521 -24 308 362 273 13.295 5.038 34.721 1,000 15:23 273 1863 1624 2300 -110 9113 6 273 10.719 5848 35.259 1,000 16:10 273 1593 2158 2365 -162 292 122 273 12.419 4.148 35.354 1,000 1.16 273 1904 1980 2198 -139 285 181 273 11.109 4559 35548 1,000 15:18 273 1843 2001 1925 -141 74 - 2 2 7 274 15.634 5612 31.926 1,000 15:31 274 1559 1940 2317 361 383 247 274 16.221 4,318 31.518 1,000 15:37 274 1476 1723 2642 32,557 156 274 15.953 3284 32.588 1,000 14.67 274 972 1877 27 26 -113 265 302 274 16.310 3.476 33.770 1,000 15.98 274 1668 1677 2728 126 143 193 274 17742 4,556 31.356 1,000 17:41 274 1487 2019 3112 235 945 725 274 18.362 3.280 31334 1,000 3.18 274 1839 1961 3052 293 840 188 275 15.395 2.133 32.182 1. 000 15:58 275 1646 1857 2417 -182 462 2 6 1

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9SO3860

ATÓM 1892 CA VAL n - .. / Ξ 1 5. 15S Anisa 1S 92 C A VAL 27 p 1 681 ATÓM 1893 C VAL 2 7 5 16.454 Anisa 1893 C VAL 275 1805 ATÓM 1894 ABOUT VAL 275 16.623 Anisa 1894 ABOUT VAL 275 2037 ATÓM 1895 CS VAL 275 14.227 Anisa 1895 CB VAL 275 1635 ATÓM 1896 CG1 VAL 275 14.080 Anisa 1896 CC-1 VAL 275 2045 ATÓM 1897 CG2 VAL 275 12.847 Anisa 1897 CC-2 VAL 275 1650 ATÓM 1898 N PRO 276 17.437 Anisa 1898 N PRO 276 1927 ATÓM 1899 CA PRO 276 18707 Anisa 1899 C A PRO 276 1736 ATÓM 1900 C PRO 276 19.382 Anisa 1900 C PRO 276 1998 ATÓM 1901 ABOUT PRO 276 19.963 Anisa 1901 ABOUT PRO 276 2015 ATÓM 1902 CB PRO 276 19.590 Anisa 1902 CB PRO 276 2094 ATÓM 1903 CG PRO 276 18.852 Anisa 1903 CG PRO 276 2051 ATÓM 1904 CD PRO 276 17446 Anisa 1904 CD PRO 276 2053 ATÓM 1905 N LEU 277 19.325 Anisa 1905 N LEU 277 1571 ATÓM 1906 CA LEU 277 19.962 Anisa 1906 CA LEU 277 2035 ATÓM 1907 C LEU 277 19.214 Anisa 1907 C LEU 277 1963 ATÓM 1908 ABOUT LEU 277 19.815 Anisa 1908 ABOUT LEU 277 2466 ATÓM 1909 CB LEU 277 20.094 Anisa 1909 CB LEU 277 2739 ATÓM 1910 CG LEU 277 20.910 Anisa 1910 CG LEU 277 3662 ATÓM 1911 CD1 LEU 277 22,396 Anisa 1911 CD1 LEU 277 3764 ATÓM 1912 CD2 LEU 277 20.708 Anisa 1912 CD2 LEU 277 4023 ATÓM 1913 N ALA 278 17.875 Anisa 1913 N ALA 278 2015 ATÓM 1914 CA ALA 278 17.124 Anisa 1914 CA ALA 278 2200 ATÓM 1915 C ALA 278 17.575 Anisa 1915 C ALA 278 1849 ATÓM 1916 ABOUT ALA 278 17.718 Anisa 1916 ABOUT ALA 278 1963 ATÓM 1917 CB ALA 278 15.642 Anisa 1917 CB ALA 278 2109 ATÓM 1918 N ARG 279 17.724 Anisa 1918 N ARG 279 2322 ATÓM 1919 CA ARG 279 18.099 Anisa 1919 CA ARG 279 2377 ATÓM 1920 C ARG 279 19.477 Anisa 1920 C ARG 279 2491 ATÓM 1921 ABOUT ARG 279 19.687 Anisa 1921 ABOUT ARG 279 3615 ATÓM 1922 CB ARG 279 18.164

1,033 33. 137 1. 000 1 5. ó 5 1800 2 4 o · 5 -180 2OI, 2 ô 5 0445 33.659 1. 000 15:33 1881 2139 116 392 - 4 5 0.280 34871 1,000 15.68 1655 2 2 ó 7 6,297,196 -0.004 32.483 1,000 5.16 1708 2755 -76 405 2 1 -1. 186 33.426 1,000 4.17 1688 2 74 0 -211 230 1 5 0608 32.203 1,000 18:45 2432 2928 -57 135 2 6 9 0093 32.844 1,000 16:21 1700 2532 97 588 3 6 -0,434 33.399 1,000 18:10 2115 3 02 5 147 616 - 9 3 0541 34.321 1,000 17:52 1961 2697 97,469 2 3 9 0171 35.348 1,000 19.66 2409 3 04 7 24 280 468 -0,796 32.214 1. 000 2 0.80 2687 3123 306 771 - 2 4 9 -0,390 30.999 1,000 2 1.57 3098 3 04 6 340 802 - 2 8 8 -0.021 31368 1,000 18:17 2306 2546 179 832 - 3 18 1.845 34.C27 1,000 9.17 1898 3025 230 511 1 0 7 2,802 34.940 1,000 19:34 2141 3171 -219 218 2 6 2 2,858 36.249 1,000 18:34 1958 3049 -33 -3-31 B 2.957 37.319 1,000 19:29 1710 3154 -271 -188 - 2 4.178 34.291 1,000 2 1.41 2011 3383 14 12 2 8 7 5192 35.111 1,000 6.34 2367 3978 -980 -547 9 4 4 4839 35.069 1,000 3 8.04 3171 7518 -487 -2,057 8 5 3 6,607 34.631 1,000 3 1.98 2018 6109 -366 508 7 3 2 2.711 36.202 1,000 17:30 1766 2793 74 218 115 2.712 37.464 1,000 16.75 1566 2600 216 146 - 2 1.523 38.313 1,000 16:31 1553 2794 -337 -196 1 0 7 1.635 39.523 1,000 17:26 1839 2754 -62 -53 2 0 5 2,622 37.177 1,000 17:55 1880 2679 295 195 - 1 1 0362 37.696 1,000 7.17 1399 2766 -178 26 3 0 8 -0,829 38473 1,000 16.93 1734 2323 14 -241 2 0 3 -0,587 39098 1,000 19.87 2292 2766 -487 -384 5 4 3 -0,974 40234 1,000 3 3.04 4823 4115 -1,726 - 1700 2 6 0 3 -2,042 37.517 1,000 2 0.04

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98'03860

ANISCU 1922 C3 ARG 279 2042 1609 3964 103 - 2 2 1 - 3 0 5 ATÓM 1923 CG ARG 279 16.742 -2,491 37.179 1. 000 2Ό- »7 7 Anisa 1923 CG ARG 279 2152 2728 2997 -98 -4 01 - 3 5 1 ATÓM 1924 CD ARG 279 16.601 -3,422 35.990 1 .000 2 4.81 Anisa 1924 CD ARG 279 3213 2982 323 1 - 1 -508 - 6 0 9 ATÓM 1925 NE ARG 279 17.575 -4,484 36.195 1. 000 2 7.50 Anisa 1925 NE ARG 279 4331 2656 3463 355 -146 - 18 1 ATÓM 1926 CZ ARG 279 17.301 -5,725 36.620 1. 000 4 1.33 Anisa 1926 CZ ARG 279 7720 2466 5519 -186 -454 - 14 2 ATÓM 1927 NNL ARG 279 16.024 -6,012 36.866 1,000 4 0.58 Anisa 1927 NH1 ARG 279 8821 3012 3585 -1,564 507 4 5 2 ATÓM 1928 NH2 ARG 279 18.200 -6,688 36.807 1,000 5 3.27 Anisa 1928 NH2 ARG 279 9516 2227 8496 -127 -4,607 -463 ATÓM 1929 N GLU 280 20.390 0119 38.424 1,000 19.68 Anisa 1929 N GLU 280 2172 2276 3028 83 324 1 3 6 ATÓM 1930 CA GLU 280 21.748 0334 38.948 1,000 2 0.28 Anisa 1930 CA GLU 280 2046 2274 3385 25,581 115 ATÓM 1931 C GLU 280 21.705 1.257 40182 1. 000 2 0.67 Anisa 1931 C GLU 280 2334 1968 3552 -281 285 2 0 ATÓM 1932 ABOUT GLU 280 22.723 1.079 40.908 1,000 6.81 Anisa 1932 ABOUT GLU 280 2659 3419 4107 -37 -183 - 8 7 ATÓM 1933 CB GLU 280 22.651 1,029 37.926 1,000 24.69 Anisa 1933 CB GLU 280 2778 2558 4044 -351 1022 3 0 3 ATÓM 1934 CG GLU 280 22.997 0342 36.634 1,000 27.13 Anisa 1934 CG GLU 280 2605 4888 2816 596 116 6 2 3 ATÓM 1935 CD GLU 280 23.815 1.298 35.760 1,000 4 3.10 Anisa 1935 CD GLU 280 4693 7780 3903 -1328 1206 8 3 4 ATÓM 1936 OE1 GLU 280 24.541 2,171 36296 1,000 4 1.36 Anisa 1936 OE1 GLU 280 2666 6033 7015 27 1099 6 0 0 ATÓM 1937 OE2 GLU 280 23.727 1.219 34.520 1,000 64.81 Anisa 1937 OE2 GLU 280 10844 10028 3751 -2,356 1103 2 1 3 4 ATÓM 1938 N CYS 281 20.777 2,156 40.313 1,000 2 1.61 Anisa 1938 N CYS 281 2372 2240 3599 -211 532 - 2 3 8 ATÓM 1939 CA CYS 281 20.481 3164 41337 1,000 24.33 Anisa 1939 CA CYS 281 2114 2911 4219 -526 1121 - 8 17 ATÓM 1940 C CYS 281 19.858 2568 42.585 1,000 27.11 Anisa 1940 C CYS 281 2492 3261 4546 -1608 1457 - 1343 ATÓM 1941 ABOUT CYS 281 19.789 3.161 43.685 1,000 19:19 Anisa 1941 ABOUT CYS 281 1997 2012 3282 -250 -326 1 3 5 ATÓM 1942 CB CYS 281 19.632 4438 40.795 1,000 2 2.02 Anisa 1942 CB CYS 281 1214 3088 4063 -286 100 - 2 10 8 ATÓM 1943 SG CYS 281 20.639 5092 39.444 1,000 5 3.41 Anisa 1943 SG CYS 281 10822 4742 4730 -3,261 1316 4 5 ATÓM 1944 N GLY 282 19.370 1.317 42.565 1,000 18.81 Anisa 1944 N GLY 282 1230 2224 3695 3 -149 - 2 0 7 ATÓM 1945 CA GLY 282 18.675 0.750 43.744 1,000 7.17 Anisa 1945 CA GLY 282 1544 1771 3171 -552 - 1 6 8 ATÓM 1946 C GLY 282 17.194 0496 43538 1,000 14.91 Anisa 1946 C GLY 282 1601 1645 2417 -135 -453 3 7 8 ATÓM 1947 0 GLY 282 16.480 -0.062 44.380 1,000 16:38 Anisa 1947 ABOUT GLY 282 1998 1921 2306 -211 -399 3 6 0 ATÓM 1948 N PHE 283 16.625 0919 42404 1,000 13:44 Anisa 1948 N PHE 283 1563 1539 2006 -189 -336 - 115 ATÓM 1949 CA PHE 283 15.173 0829 42.203 1,000 14:52 Anisa 1949 C A PHE 283 1677 1410 2428 -187 -670 4 6 ATÓM 1950 C PHE 283 14.810 -0,604 41.809 1,000 8.13 Anisa 1950 C PHE 283 1519 1314 2137 -121 -338 1 7 4 ATÓM 1951 ABOUT PHE 283 15.311 -1,184 40.837 1,000 14:11 Anisa 1951 ABOUT PHE 283 1366 1418 2578 -142 -78 1 7 ATÓM 1952 CB PHE 283 14.749 1,800 41.078 1,000 13.76 Anisa 1952 CB PHE 283 1814 1288 2125 -39 -268 0

SUBSTITU11 SHEET (RULE 26)

WO 99'33994 rCT.'GB9S / 03860

ATÓM 1953 CG PHL 28 3 14 N 4 2 3,269 41.512 1. 000 14.75 Anisa 1953 C G PHE 2S3 1985 1363 225 5 12 -3: 12 _ - 3 ATÓM 1954 CD1 PHE 2S3 13.814 3,904 42. 142 1,000 2 1.50 Anisa 1954 CD1 PHE 283 2318 1759 409 1 303 -23 - 6 2 6 ATÓM 1955 CD2 PHE 283 15.994 3. 999 41 .298 1,000 17.72 Anisa 1955 CD2 PHE 283 2526 1244 2953 -307 -89 2 7 2 ATÓM 1956 CE1 PHE 283 13.909 5. 177 42.655 1,000 2 0.78 Anisa 1956 CE1 PHE 283 2056 1802 40 3 6 92 65 - 6 4 6 ATÓM 1957 CE2 PHE 283 16.115 5.290 41.814 1,000 6.15 Anisa 1957 CE2 PHE 283 2101 1257 2 3 <5 5 -5 -255 3 6 7 ATÓM 1958 CZ PHE 283 15.084 5.891 42.506 1,000 1 S. 0 4 Anisa 1958 CZ PHE 283 1881 1995 2 97 9 192 -432 2 0 ATÓM 1959 N ASP 284 13.883 -1,178 42 .579 1,000 7.13 Anisa 1959 N ASP 284 1549 1366 2049 -73 -331 1 1 7 ATÓM 1960 CA ASP 284 13.502 -2,584 42 395 1,000 12.80 Anisa 1960 C A ASP 284 1481 1460 19 2 4 -231 -207 1 5 7 ATÓM 1961 C ASP 284 12.335 -2,654 41421 1,000 12.88 Anisa 1961 C ASP 284 1493 1508 1891 -19 -180 - 5 5 ATÓM 1962 ABOUT ASP 284 11.231 -3,147 41.741 1,000 13.69 Anisa 1962 ABOUT ASP 284 1407 1351 2442 -93 -281 9 2 ATÓM 1963 CB ASP 284 13.141 -3,203 43.744 1,000 14:10 Anisa 1963 CB ASP 284 1966 1534 1858 -40 -11 1 4 5 ATÓM 1964 CG ASP 284 13.165 -4,730 43.717 1,000 14:49 Anisa 1964 CG ASP 284 1906 1520 2 07 9 47 -424 2 9 0 ATÓM 1965 OD1 ASP 284 13.732 -5.305 42.758 1,000 14.81 Anisa 1965 OD1 ASP 284 2036 1343 2250 -152 -166 2 3 1 ATÓM 1966 OD2 ASP 284 12.652 -5,310 44.696 1,000 15:32 Anisa 1966 OD2 ASP 284 1979 1557 2286 -79 -109 1 5 3 ATÓM 1967 N VAL 285 12.644 -2,191 40217 1,000 12:40 Anisa 1967 N VAL 285 1582 1260 1870 79 -185-1 1 3 1 ATÓM 1968 CA VAL 285 11.599 -2,064 39.216 1,000 12:31 Anisa 1968 CA VAL 285 1442 1469 1767 -161 -59 - 1 ATÓM 1969 C VAL 285 11.229 -3,419 38.589 1,000 9.12 Anisa 1969 C VAL 285 1220 1407 1967 -1 -100 - 7 ' 9 ATÓM 1970 ABOUT VAL 285 12.085 -4,311 38433 1,000 13.68 Anisa 1970 ABOUT VAL 285 1237 1514 2446 67 56 4 0 ATÓM 1971 CB VAL 285 12.009 -1,066 38.098 1,000 14.68 Anisa 1971 CB VAL 285 1943 1621 2014 -163 -50 2 5 9 ATÓM 1972 CG1 VAL 285 12.131 0332 38.672 1,000 8.17 Anisa 1972 CG1 VAL 285 2429 1402 2658 18 -465,425 ATÓM 1973 CG2 VAL 285 13.309 -1,499 37,433 1,000 15.69 Anisa 1973 CG2 VAL 285 2131 2180 1649 -316 161 3 0 6 ATÓM 1974 N SER 286 9952 -3,541 38241 1,000 12:24 Anisa 1974 N SER 286 1263 1440 1946 -12 -148 - 117 ATÓM 1975 CA SER 286 9.398 -4,669 37495 1,000 12.84 Anisa 1975 CA SER 286 1571 1463 1845 -356 -30 1 4 ATÓM 1976 C SER 286 8.861 -4,118 36.172 1,000 11.99 Anisa 1976 C SER 286 1516 1374 1666 -28 60 - 19 8 ATÓM 1977 ABOUT SER 286 7654 -4,110 35.917 1,000 15.68 Anisa 1977 ABOUT SER 286 1514 2384 2059 2 18 - 2 0 ATÓM 1978 CB SER 286 8.301 -5,327 38.300 1,000 12:54 Anisa 1978 CB SER 286 1407 1442 1915 -59 170 - 5 5 ATÓM 1979 OG SER 286 7415 -4,380 38.890 1,000 13:15 Anisa 1979 OG SER 286 1531 1430 2034 105 -73 - 5 9 ATÓM 1980 N LEU 287 9.769 -3,649 35. 333 1,000 13:56 Anisa 1980 N LEU 287 1574 1521 2058 41,133,177 ATÓM 1981 CA LEU 287 9.451 -2,932 34.101 1,000 13:48 Anisa 1981 CA LEU 287 1812 1418 1891 -84 116 1 7 ATÓM 1982 C LEU 287 10.075 -3,654 32.908 1,000 15:12 Anisa 1982 C LEU 227 1945 1714 2086 33 233 - 3 1 ATÓM 1983 ABOUT LEU 287 11.277 -3,883 32.927 1. 000 17.91

SUBSTITUTE SHEET (RULE 26)

WO 99 '33994

PCT / GB9S / 03860

Anisa 2 99 3 0 LE'J 287 1865 2 2 75 2645 109 300 -275 ATÓM 19S4 CB LEU 287 9954 -1,480 34116 1. 000 7 Anisa 1984 CB LEU 287 1773 1380 2306 -34 24S 107 ATÓM 1985 CG LEU 287 9.362 -0,603 35231 1. 000 14:32 Anisa 198 5 CG LEU 287 1421 1496 2523 62 52 -15 8 ATÓM 1986 CDI LEU 287 10.143 0705 35.413 1,000 14:53 Anisa 1986 CDI LEU 287 1672 1444 2403 -146 143 ATÓM 1987 CD2 LEU 287 7.921 -0,197 34.820 1,000 3.16 Anisa 1987 CD2 LEU 287 1476 2035 2579 166 -100 - 7 ATÓM 1988 N ASP 288 9.256 -4,060 31.958 1,000 9.15 Anisa 1988 N ASP 288 2041 1611 2081 73 175 i - 2 1 7 ATÓM 1989 CA ASP 288 9,764 -4. 722 30757 1,000 16:55 .ANISOU 1989 CA ASP 288 1992 2028 2268 29 335 > -314 ATÓM 1990 C ASP 288 10.437 -3,682 29.874 1,000 18.74 Anisa 1990 C ASP 288 2484 2597 2040 -231 97 8 1 ATÓM 1991 0 ASP 288 9.998 -2,526 29.849 1,000 2 5-48 Anisa 1991 0 ASP 288 3382 2433 3865 -322 639 346 ATÓM 1992 CB ASP 288 8659 -5,490 30.060 1. 000 19:23 Anisa 1992 CB ASP 288 2431 2414 2460 -209 258-7 2 0 ATÓM 1993 CG ASP 288 9.139 -6,468 29.000 1,000 19:50 Anisa 1993 CG ASP 288 2688 2223 2499 -49 394 - 5 5 2 ATÓM 1994 OD1 ASP 288 10.173 -7,145 29.185 1,000 2 7.03 Anisa 1994 OD1 ASP 288 3134 3038 4100 624 427-7 1 6 ATÓM 1995 OD2 ASP 288 8.458 -6,566 27.955 1,000 3 1.00 Anisa 1995 OD2 ASP 288 3596 4859 3325 307 -361 -2100 ATÓM 1996 N GLY 289 11.489 -4,035 29.137 1,000 2 2.68 Anisa 1996 N GLY 289 2960 2893 2765 -531 778 116 ATÓM 1997 CA GLY 289 12.008 -3,083 28.169 1,000 2 5.60 Anisa 1997 CA GLY 289 3678 3562 2486 -1469 558 1 1 ATÓM 1998 C GLY 289 12.988 -2,078 28725 1,000 2 1.08 Anisa 1998 C GLY 289 2567 2916 2528 -485 353 150 ATÓM 1999 0 GLY 289 13.411 -2,097 29.891 1,000 2 3.72 Anisa 1999 0 GLY 289 3428 3219 2364 -1104 440 113 ATÓM 2000 N GLU 290 13.402 -1,168 27.818 1,000 18:32 Anisa 2000 N GLU 290 2246 2396 2319 -145 616-115 ATÓM 2001 CA GLU 290 14.538 -0,301 28074 1,000 17.75 Anisa 2001 CA GLU 290 1912 2419 2412 97 770 3 6 7 ATÓM 2002 C GLU 290 14.261 1,058 28.696 1,000 17.90 Anisa 2002 C GLU 290 2180 2308 2313 50,711 - 2,97 ATÓM 2003 0 GLU 290 15.143 1.619 29353 1,000 17:58 Anisa 2003 0 GLU 290 2525 2050 2104 -35 380 165 ATÓM 2004 CB GLU 290 15.341 -0,161 26785 1,000 3.21 Anisa 2004 CB GLU 290 3184 2508 3126 -273 1753 - 4 7 6 ATÓM 2005 CG GLU 290 15.833 -1,492 26.226 1,000 2 4.55 Anisa 2005 CG GLU 290 3609 2992 2725 348 1233 - 7 4 3 ATÓM 2006 CD GLU 290 16.676 -2,280 27221 1,000 3 0.03 Anisa 2006 CD GLU 290 3365 3708 4337 476 753-2 2 1 1 ATÓM 2007 OE1 GLU 290 17.492 -1,684 27947 1,000 0.04 Anisa 2007 OE1 GLU 290 5043 6674 3498 525 36 - 1 2 2 7 ATÓM 2008 OE2 GLU 290 16.622 -3. 527 27237 1,000 5 1.76 Anisa 2008 OE2 GLU 290 8785 3812 7070 -12 -482 1 5 8 3 ATÓM 2009 N THR 291 13.064 1. 578 28486 1,000 18:14 Anisa 2009 N THR 291 2305 2486 2103 224 711 -321 ATÓM 2010 CA THR 291 12.697 2896 29.049 1,000 18.72 Anisa 2010 CA THR 291 2521 2080 2511 105 1132 6 6 ATÓM 2011 C THR 291 11.278 2.744 29593 1,000 15.79 Anisa 2011 C THR 291 2178 1758 2064 134 538-5 5 ATÓM 2012 0 THR 291 10.517 1,834 29.217 1,000 18.62 Anisa 2012 0 THP. 291 2764 1966 2344 -248 663 - 3 1 1 ATÓM 2013 CB THP. 291 12.722 4031 28.044 1,000 1.54 Anisa 2013 CB THP. 291 304 3 2625 2516 -164 891 362

SUBSTTTUTE SHEET (RULE 26)

WO 99.33994

PCT / GB9SO3S60

ATÓM 2014 OG1 T H R 2 91 i 1. 695 Anisa 2014 OG1 THR 291 3160 ATÓM 2015 CG2 THR 291 14.048 Anisa 2015 CG2 THR 291 3199 ATÓM 2016 N ALA 292 10.959 Anisa 2016 N ALA 292 1637 ATÓM 2017 C A ALA 292 9. 675 Anisa 2017 C A ALA 292 1488 ATÓM 2018 C ALA 292 9.356 Anisa 2018 C ALA 292 1334 ATÓM 2019 ABOUT ALA 292 10.228 Anisa 2019 ABOUT ALA 292 1529 ATÓM 2020 CB ALA 292 9.670 Anisa 2020 CB ALA 292 1693 ATÓM 2021 N THR 293 8054 Anisa 2021 N THR 293 1468 ATÓM 2022 CA THR 293 7605 Anisa 2022 C A THR 293 1565 ATÓM 2023 C THR 293 7407 Anisa 2023 C THR 293 1345 ATÓM 2024 ABOUT THR 293 7214 Anisa 2024 ABOUT THR 293 1385 ATÓM 2025 CB THR 293 6295 Anisa 2025 CB THR 293 1598 ATÓM 2026 OG1 THR 293 5273 Anisa 2026 OG1 THR 293 1672 ATÓM 2027 CG2 THR 293 6.476 Anisa 2027 CG2 THR 293 2121 ATÓM 2028 N PHE 294 7.241 Anisa 2028 N PHE 294 1607 ATÓM 2029 CA PHE 294 6.857 Anisa 2029 CA PHE 294 1332 ATÓM 2030 C PHE 294 5.556 Anisa 2030 C PHE 294 1336 ATÓM 2031 ABOUT PHE 294 5.403 Anisa 2031 ABOUT PHE 294 1556 ATÓM 2032 CB PHE 294 6698 Anisa 2032 CB PHE 294 2039 ATÓM 2033 CG PHE 294 6306 Anisa 2033 CG PHE 294 1786 ATÓM 2034 CD1 PHE 294 7207 Anisa 2034 CD1 PHE 294 2132 ATÓM 2035 CD2 PHE 294 4,964 Anisa 2035 CD2 PHE 294 2156 ATÓM 2036 CE1 PHE 294 6.810 Anisa 2036 CE1 PHE 294 2348 ATÓM 2037 CE2 PHE 294 4591 Anisa 2037 CE2 PHE 294 2078 ATÓM 2038 CZ PHE 294 5,507 Anisa 2038 CZ PHE 294 2443 ATÓM 2039 N GLN 295 4,588 Anisa 2039 N GLN 295 1248 ATÓM 2040 CA GLN 295 3. 320 Anisa 2040 C A GLN 295 1266 ATÓM 2041 C GLN 295 3,512 Anisa 2041 C GLN 295 1449 ATÓM 2042 0 GLN 295 2922 Anisa 2042 ABOUT GLN 295 1323 ATÓM 2043 CB GLN 295 2.375 Anisa 2043 CB GLN 295 1227 ATÓM 2044 CG GLN 295 1.062

3862 27077 2. 000 2 5. 9 Ξ 4 072 264 1 - 8 6 7-3> S 0 3 4115 27.292 1,000 4.20 3 832 2164 -445 930 533 3. 658 30.492 1,000 14.84 1656 234 7 200 428 - 1 5 3 3 .057 31. 179 1,000 13.84 1477 2294 170 299 7 8 5. 065 31619 1,000 12.65 1564 1938 60 144-1 3 9 5939 31.710 1,000 14:27 1596 22'95 -35 109 116 2.754 32.414 1,000 2.14 1580 2053 37 22 -27 5258 31 .916 1,000 13:54 1617 2 05 8 117 373-1 1 8 6. 546 32 424 1,000 13:40 1647 18''7 152 208 - 2 3 2 6482 33.952 1,000 9.12 1322 1927 -62 325 - 1 2 5.441 34.555 1,000 12.93 1356 2170 -190 194 9 0 7.058 31.788 1,000 13:45 1579 1925 95 345 345 6.112 32.117 1,000 13.75 1570 1981 -12 314 135 7.139 30.272 1,000 15.93 2022 1911 255 434 337 7.661 34.544 1,000 12.81 1440 1822 -83 149 -15 1 7773 35.935 1,000 12:37 1469 1899 -267 166-2 8 9 7.022 36.184 1,000 12:36 1361 1999 -151 30-36 6.253 37.143 1,000 13:27 1410 2076 -191 183 4 6 9271 36267 1,000 13.83 1351 1866 -192 -29 - 17 7 9.488 37711 1,000 13:10 1216 1974 -125 -63 - 2 3 4 9.411 38.749 1,000 17:41 2533 1952 -1012 -286 7 6 9.739 38.026 1,000 18:41 2263 2575 565 332 5 7 9608 40.054 1,000 17.72 2296 2086 -308 -362 - 1 3 7 10.010 39.324 1,000 19:37 2541 2740 330 232-6 6 0 9956 40.355 1,000 18:36 1678 2855 -394 - 55 - 2 4 5 7.205 35.246 1,000 12:59 1429 2105 -62 38 - 16 8 6484 35408 1,000 12.76 1215 2365 7 -157-11 11 4. 984 35.318 1,000 12:24 1256 194 4 10 1 - 7 3 4238 36.L01 1,000 13.61 1427 242 1 7 85 15 5 6.975 34.317 1,000 14:31 1594 2 615 81-133 192 6,256 34.249 1,000 14 .03

SUBSTTTUTE SHEET (RULE 26)

WO99 / 33O94

PCT / GB98 / 03860

.ANISOU 2044 C G GLN 2 9 5 1391 150 9 243 0 - G -300 4 7 ATÓM 2045 CD GLN 295 0157 3687 33115 1. 000 1? 6 Anisa 2045 CD GLN 295 1305 148Ó 2361 133 -117 165 ATÓM 2046 OE1 GLN 295 0.459 7. 693 32.419 1. 000 15:35 Anisa 2046 OE1 GLN 295 1811 1651 2371 161 206 220 ATÓM 2047 NE2 GLN 295 -0,982 6.02 ó 32.943 1. 000 4.15 Anisa 2047 NE2 GLN 295 1225 1995 2493 75 -139-9 9 ATÓM 2048 N ASP 296 4 .363 4.463 34.423 1,000 12.66 Anisa 2048 N ASP 296 1425 13 96 1990 181 -112 - 1 0 0 ATÓM 2049 CA ASP 296 4. 653 3,016 34.439 1,000 12:26 Anisa 2049 C A ASP 296 1628 1274 1755 53 -51 -151 ATÓM 2050 C ASP 296 5.167 2. 569 35.792 1,000 11:57 Anisa 2050 C ASP 296 1199 1300 1895 -82 30-22 ATÓM 2051 ABOUT ASP 296 4.854 1. 460 36.224 1,000 8.13 Anisa 2051 ABOUT ASP 296 1534 1368 2070 -107 38139 ATÓM 2052 CB ASP 296 5709 2,634 33.399 1,000 14:18 Anisa 2052 CB ASP 296 1870 1700 1819 141 30 - 3 7 7 ATÓM 2053 CG ASP 296 5295 2,848 31.952 1,000 13:32 Anisa 2053 CG ASP 296 1655 1557 1848 -58 67 2 ATÓM 2054 OD1 ASP 296 4.110 2,725 31.601 1,000 15.83 Anisa 2054 OD1 ASP 296 1680 1935 2402 -68 -126 - 18 9 ATÓM 2055 OD2 ASP 296 6.212 3.098 31.114 1,000 15:27 Anisa 2055 OD2 ASP 296 1757 1937 2106 -229 137 177 ATÓM 2056 N TRP 297 6038 3352 36.416 1,000 12:26 Anisa 2056 N TRP 297 1325 1403 1931 -34 - 123 - 1 1 8 ATÓM 2057 CA TRP 297 6.683 2,960 37.656 1,000 12.82 Anisa 2057 CA TRP 297 1328 1599 1943 -104 -49 151 ATÓM 2058 C TRP 297 5.746 3.007 38.858 1,000 13:13 Anisa 2058 C TRP 297 1418 1580 1992 24 -23 185 ATÓM 2059 ABOUT TRP 297 5.565 2.030 39.584 1,000 3.14 Anisa 2059 ABOUT TRP 297 1554 1619 2159 102 137 320 ATÓM 2060 CB TRP 297 7908 3,847 37.928 1,000 13.68 Anisa 2060 CB TRP 297 1130 1692 2376 -19 -169 151 ATÓM 2061 CG TRP 297 8.646 3.455 39.166 1,000 13:28 Anisa 2061 CG TRP 297 1143 1646 2255 91 -96 2 2 ATÓM 2062 CD1 TRP 297 8.932 2,179 39.622 1,000 15:58 Anisa 2062 CD1 TRP 297 1615 1689 2618 275 -544 - 7 7 ATÓM 2063 CD2 TRP 297 9.144 4 .353 40.189 1,000 14.69 Anisa 2063 CD2 TRP 297 1327 1693 2562 -117 -219 5 ATÓM 2064 NE1 TRP 297 9.583 2 .265 40.840 1,000 15:34 Anisa 2064 NE1 TRP 297 1378 1853 2598 70 -494 7 5 ATÓM 2065 CE2 TRP 297 9724 3597 41.203 1,000 16:13 Anisa 2065 CE2 TRP 297 1241 2009 2880 182 -676-1 9 6 ATÓM 2066 CE3 TRP 297 9.094 5,756 40.284 1,000 2.13 Anisa 2066 CE3 TRP 297 3040 1658 3712 -665 -1408 129 ATÓM 2067 CZ2 TRP 297 10.318 4,180 42.316 1,000 18:45 Anisa 2067 CZ2 TRP 297 2204 2387 2418 -326 - 3 3 1 ATÓM 2068 GB3 TRP 297 9.670 6353 41.399 1,000 2 1.55 Anisa 2068 GB3 TRP 297 2916 2104 3167 -55 - 752 - 4 5 8 ATÓM 2069 CH2 TRP 297 10.258 5.546 42.397 1,000 2 3.53 Anisa 2069 CH2 TRP 297 3298 2356 3285 -320 -1145 - 3 4 4 ATÓM 2070 N ILE 298 5106 4.167 39044 1,000 13:58 Anisa 2070 N ILE 298 1324 1726 2108 241 -167 127 ATÓM 2071 CA ILE 298 4.299 4.440 40.229 1,000 14.68 Anisa 2071 C A ILE 298 1413 2177 1986 -13 -161-2 2 0 8 ATÓM 2072 C ILE 298 2841 4. 054 40.121 1,000 2.12 Anisa 2072 C ILE 298 1455 1300 1813 56 -239 402 ATÓM 2073 0 ILE 298 2 .182 3 .782 41 .147 1. 000 13.67 Anisa 2073 ABOUT ILE 298 1732 1582 1881 -23 -4,193 ATÓM 2074 CB ILE 298 4428 5,914 40.673 1. 000 19:45 Anisa 2074 CB ILE 298 2261 24 4 6 2683 -699 2 3 7 - 8 4 5

SUBSTITUTE SHEET (RULE 26)

WO 99'3309-4

PCT / GB9S'O3SbO

ATÓM ? C75 CG1 ILE 298 5 907 6.245 • 1 1.001 1. 000 2 7 N 3 Anisa 2075 CG1 ILE 2 98 2776 4275 3 5 2 5 - 1315 -3K '-10 3 0 ATÓM 207 6 CG2 ILE 2 98 3679 6 .319 41 9291.000 2 5.05 Anisa 2076 CG2 ILE 298 3770 3344 2405 -57 255-9 8 3 ATÓM 2077 CD1 ILE 298 6.368 5.628 42.306 1.000 4 3.32 Anisa 2077 CD1 ILE 298 4561 7224 4674 -652 -1890 -117 ATÓM 2078 N GLY 299 2.317 3. 980 38.893 1.000 12:16 Anisa 2078 N GLY 299 1432 1308 1879 78 -304 106 ATÓM 2079 C A GLY 299 0.918 3.741 38.670 1.000 12.98 Anisa 2079 C A GLY 299 1276 1279 2379 106 -18S-1 5 4 ATÓM 2080 C GLY 299 0135 5017 38.378 1.000 9.13 Anisa 2080 C GLY 299 1421 1403 2151 113 -231 118 ATÓM 2081 ABOUT GLY 299 0738 6.025 38.017 1.000 14:00 Anisa 2081 ABOUT GLY 299 1713 1353 2252 122 289-1 ATÓM 2082 N GLY 300 -1,183 4.917 38.447 1.000 8.13 Anisa 2082 N GLY 300 1325 1545 2099 146 -267 - 1 5 ATÓM 2083 C A GLY 300 -2,075 5966 37.992 1.000 13:45 Anisa 2083 CA GLY 300 1447 1521 2143 116 -415 - 1 3 4 ATÓM 2084 C GLY 300 -2,519 6.972 39.042 1.000 12.94 Anisa 2084 C GLY 300 1098 1365 2456 -52 -407-1 9 2 ATÓM 2085 ABOUT GLY 300 -3,262 7.875 38.672 1.000 13:39 Anisa 2085 ABOUT GLY 300 1321 1342 2422 -19 -217 - 5 4 ATÓM 2086 N ASN 301 -1,973 6.845 40.254 1.000 13:35 Anisa 2086 N ASN 301 1494 1429 2151 -225 -232 - 1 0 0 ATÓM 2087 CA ASN 301 -2,162 7.842 41.313 1.000 13.83 Anisa 2087 CA ASN 301 1590 1435 2230 -194 -38 - 6 1 ATÓM 2088 C ASN 301 -0,837 8.254 41.885 1.000 12:46 Anisa 2088 C ASN 301 1676 1268 1791 -35 -142-2 0 ATÓM 2089 ABOUT ASN 301 -0.007 7.405 42.169 1.000 13.89 Anisa 2089 ABOUT ASN 301 1831 1355 2092 73 -144 - 1 3 ATÓM 2090 CB ASN 301 -3,075 7238 42.360 1.000 1.16 Anisa 2090 CB ASN 301 1632 1909 2542 77 224 315 ATÓM 2091 CG ASN 301 -3,942 8199 43.136 1.000 18:23 Anisa 2091 CG ASN 301 1986 2508 2435 190 152-9 0 ATÓM 2092 OD1 ASN 301 -4,973 8.690 42.614 1.000 17:44 Anisa 2092 OD1 ASN 301 1606 1626 3394 -21 144 - 1 8 0 ATÓM 2093 ND2 ASN 301 -3,518 8454 44.338 1.000 3 3.30 Anisa 2093 ND2 ASN 301 2804 6923 2928 1012 -230 - 1 2 3 ATÓM 2094 N TYR 302 -0,595 9.564 42.073 1.000 12.96 Anisa 2094 N TYR 302 1662 1278 1985 -69 -21 -135 ATÓM 2095 CA TYR 302 0674 9948 42.702 1.000 13:48 Anisa 2095 CA TYR 302 1673 1259 2192 -130 -132 3 4 ATÓM 2096 C TYR 302 0768 9269 44.078 1.000 12.63 Anisa 2096 C TYR 302 1413 1293 2091 53 44 1 9 ATÓM 2097 ABOUT TYR 302 -0,218 9.151 44.806 1.000 14:15 Anisa 2097 ABOUT TYR 302 1332 1737 2305 -65 48-27 ATÓM 2098 CB TYR 302 0764 11.472 42.916 1.000 13:30 Anisa 2098 CB TYR 302 1635 1192 2226 -81 33 4 1 ATÓM 2099 CG TYR 302 1.159 12.143 41.619 1.000 2.12 Anisa 2099 CG TYR 302 1586 1103 1880 -59 -25-2 2 7 1 ATÓM 2100 CD1 TYR 302 2.501 12.233 41.275 1.000 13:11 Anisa 2100 CD1 TYR 302 1633 1284 2066 -80 11-18 ATÓM 2101 CD2 TYR 302 0.235 12.709 40.739 1.000 12:52 Anisa 2101 CD2 TYR 302 1576 1132 2049 -44 13 - 12 7 ATÓM 2102 CE1 TYR 302 2.933 12.822 40.119 1.000 12:29 Anisa 2102 CE1 TYR 302 1581 1043 2045 -185 -84 - 7 7 ATÓM 2103 CE2 TYR 302 0637 13.273 39.53'5 1.000 14:12 Anisa 2103 CE2 TYR 302 1462 1443 2458 -241 15 3 2 5 ATÓM 2104 CZ TYR 302 1,983 13.347 39.23 L 1.000 i 12.69 Anisa 2104 CZ TYR 302 1483 1224 2113 -287 -91 1 0 ATÓM 2105 OH TYR 302 2,376 13.866 38.013 1.00C 1 13.42

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S'03S60

Anisa 2105 OH TYR 302 1505 1469 2124 -93 33146 ATÓM 2106 N VAL 303 1.956 8,855 44.450 1. 000 Γ3 -. * 9 2 Anisa 2106 N VAL 303 1406 1637 2246 154 88 9 9 ATÓM 2107 CA VAL 303 2.355 8.336 45.746 1000 1 4.5 1 Anisa 2107 C A VAL 303 1838 1320 2355 -137 -391-7 4 ATÓM 2108 C VAL 303 3.498 9.244 46.239 1. 1 5.2 Anisa 2108 C VAL 303 1404 1507 2876 -102 -105 3 4 8 ATÓM 2109 0 VAL 303 4 .471 9. 386 45.512 1,000 1 8.7 0 Anisa 2109 0 VAL 303 1859 1861 3386 -239 326 - 5 0 5 ATÓM 2110 CB VAL 303 2,856 6.880 45632 1,000 1 6.7 5 Anisa 2110 CB VAL 303 2140 1319 2905 -759 - 1 2 3 ATÓM 2111 CG1 VAL 303 3,279 6.401 47.017 1. 000 9 9.5 3 Anisa 2111 CG1 VAL 303 2185 1951 3284 232 -1054 ATÓM 2112 CG2 VAL 303 1,723 5956 45.125 1,000 1 7.8 2 Anisa 2112 CG2 VAL 303 2476 1442 2852 -213 -558 - 4 0 6 ATÓM 2113 N ASN 304 3349 9,900 47.378 1,000 1 4.0 7 Anisa 2113 N ASN 304 1409 1369 2566 -39 -407-8 6 ATÓM 2114 CA ASN 304 4.317 10.928 47772 1.000 1 4.3 1 Anisa 2114 CA ASN 304 1474 1387 2578 -102 -424 - 5 ATÓM 2115 C ASN 304 5.450 10.397 48.637 1,000 1 3.7 5 Anisa 2115 C ASN 304 1360 1487 2378 34 -274-8 7 ATÓM 2116 0 ASN 304 6539 10.962 48.584 1.000 14.60 Anisa 2116 0 ASN 304 1314 1795 2438 -34 -55 - 3 - 2 ATÓM 2117 CB ASN 304 3589 12.035 48.551 1.000 14.26 Anisa 2117 CB ASN 304 1710 1214 2494 6 -303 176 ATÓM 2118 CG ASN 304 2535 12.661 47.642 1.000 14.81 Anisa 2118 CG ASN 304 1551 1627 2449 23 -114 402 ATÓM 2119 OD1 ASN 304 2866 13.255 46.622 1.000 16.52 Anisa 2119 OD1 ASN 304 1896 1746 2636 81 19 5 8 9 ATÓM 2120 ND2 ASN 304 1.290 12.595 48.102 1.000 18.4 3 Anisa 2120 ND2 ASN 304 1560 2980 2463 127 -10 199 ATÓM 2121 N ILE 305 5.175 9.413 49.463 1.000 16.3 6 Anisa 2121 N ILE 305 1546 1553 3117 -78 -502 2 6 6 ATÓM 2122 CA ILE 305 6173 8.890 50.407 1,000 14.8 5 Anisa 2122 CA ILE 305 1670 1537 2436 165 -278 - 4 0 ATÓM 2123 C ILE 305 6.183 7.372 50352 1,000 15.7 8 Anisa 2123 C ILE 305 1527 1555 2914 95 -438-5 5 1 ATÓM 2124 0 ILE 305 5231 6736 49.886 1.000 17.54 Anisa 2124 0 ILE 305 1463 1789 3412 -131 -404 5 ATÓM 2125 CB ILE 305 5.949 9.430 51.818 1.000 17.8 0 Anisa 2125 CB ILE 305 2167 1962 2634 -23,265 - 2 0 9 ATÓM 2126 CG1 ILE 305 4578 9.091 52416 1.000 18.93 Anisa 2126 CG1 ILE 305 1716 2948 2526 1 -218 -163 ATÓM 2127 CG2 ILE 305 6171 10.944 51.823 1.000 19.17 Anisa 2127 CG2 ILE 305 2685 1863 2737 70 -533 - 4 0 5 ATÓM 2128 CD1 ILE 305 4415 9459 53.863 1.000 21.28 Anisa 2128 CD1 ILE 305 2521 2902 2662 19 451 - 7 1 ATÓM 2129 N ARG 306 7246 6.806 50.908 1.000 14.59 Anisa 2129 N ARG 306 1738 1641 2165 52 -356 2 7 1 ATÓM 2130 CA ARG 306 7424 5.360 50.828 1.000 15.25 Anisa 2130 CA ARG 306 1509 1663 2622 139 -303 7 7 ATÓM 2131 C ARG 306 8.234 4,903 52.024 1.000 15.02 Anisa 2131 C ARG 306 1588 1464 2656 133 -332-2 2 1 ATÓM 2132 0 ARG 306 9,141 5.614 52.433 1.000 16.63 Anisa 2132 0 ARG 306 1682 2101 2536 (-219) - 294 - 1 6 8 ATÓM 2133 CB ARG 306 8.135 4 .943 49.532 1.000 16.31 Anisa 2133 CB ARG 306 1820 1681 2697 -100 -270 -1 5 0 ATÓM 2134 CG ARG 306 8.226 3 .414 49.377 1,000 1 8.4 3 Anisa 2134 CG ARG 306 2476 1700 2828 -194 - 1 5 6 ATÓM 2135 CD ARG 306 8.401 3.068 47.900 1,000 1 8.2 6 Anisa 2135 CD ARG 306 2087 1971 2880 -120 -145 -330

suBSTmrre sheet (rule 24)

WO 99'33994

PCT / GB98 03860

ATÓM 2 1 3 O NO ARG 306 and 136 - 83 - 3.228 4 7 1 N 8 1,000 2 C. 5 3 Anisa 2136 NE ARG 306 24 4 2 2013 3 34 5 -577 -Έ6 3 - 2 3 4 ATÓM 2137 CZ ARG 306 6.980 3178 45.873 1,000 2 0.27 Anisa 2137 CZ ARG 306 2330 2057 33 16 373 -522 2 0 ATÓM 2138 NH1 ARG 306 8086 3,000 45. 107 1,000 2.13 Anisa 2136 NH1 ARG 306 2136 2580 3 69 5 274 -5S9 - 7 2 3 ATÓM 2139 NH2 ARG 306 5 .759 3 .250 45.341 1,000 18:44 Anisa 2139 NH2 ARG 306 2107 1838 3062 259 - 2 8 5 7 4 ATÓM 2140 N ARG 307 7.898 3. 775 52 612 1,000 19:10 Anisa 2140 N ARG 307 2716 1872 2 6 71 -294 -607 3 2 7 ATÓM 2141 C A ARG 307 8. 576 3 .212 53768 1,000 2 1.13 Anisa 2141 CA ARG 307 3321 2201 2 5 04 -48 -845 1 3 9 ATÓM 2142 C ARG 307 9536 2. 138 53.277 1,000 2 3.30 Anisa 2142 C ARG 307 3417 2170 3267 181 -1046 3 9 ATÓM 2143 ABOUT ARG 307 9.385 1. 601 52.187 1,000 2 1.01 Anisa 2143 ABOUT ARG 307 2574 2355 3052 174 -728 1 1 2 ATÓM 2144 CB ARG 307 7.557 2. 522 54.694 1,000 2 7.30 Anisa 2144 CB ARG 307 4545 3184 2645 -13 -247 7 0 5 ATÓM 2145 CG ARG 307 6.839 3488 55.629 1,000 4.30 Anisa 2145 CG ARG 307 6310 6374 4907 215 16 5 5 - 9 7 0 ATÓM 2146 CD ARG 307 7.054 3.085 57085 1,000 6 6.50 Anisa 2146 CD ARG 307 11107 10355 3806 -2,980 2792 - 114 5 ATÓM 2147 NE ARG 307 5.989 2.203 57.531 1,000 8.91 Anisa 2147 NE ARG 307 11821 12833 533 3 -4,530 1969 - 5 ATÓM 2148 CZ ARG 307 5987 1.285 58.479 1,000 7 3.67 Anisa 2148 CZ ARG 307 7704 14382 5 9 07 -4,724 1248 1 0 5 1 ATÓM 2149 NH1 ARG 307 7.063 1-038 59214 1,000 8 0.32 Anisa 2149 NH1 ARG 307 6613 17949 5955 -3,290 2179 1 0 5 ATÓM 2150 NH2 ARG 307 4872 0597 58.707 1,000 7 3.74 Anisa 2150 NH2 ARG 307 9116 15919 2 983 -6,954 438 - 9 17 ATÓM 2151 N THR 308 10.551 1,861 54.113 1,000 2 5.61 Anisa 2151 N THR 308 4234 2212 3285 536 -1421 -232 ATÓM 2152 CA THR 308 11.308 0.640 53622 1,000 3 0.02 Anisa 2152 CA THR 308 3468 1939 5996 225 -1629 -19 4 ATÓM 2153 C THR 308 10.468 -0,611 54030 1,000 5.42 Anisa 2153 C THR 308 2915 2190 4552 453 -626 - 3 2 1 ATÓM 2154 ABOUT THR 308 9.523 -0,768 54.787 1,000 3 0.10 Anisa 2154 ABOUT THR 308 4042 3482 3912 614 -217 - 12 5 ATÓM 2155 CB THR 308 12.581 0531 54688 1,000 2 6.09 Anisa 2155 CB THR 308 2701 3586 3626 242 -361 - 4 5 6 ATÓM 2156 OG1 THR 308 12.140 0751 56028 1,000 3 2.90 Anisa 2156 OG1 THR 308 4146 4188 4167 504 745 - 4 9 5 ATÓM 2157 CG2 THR 308 13.577 1.594 54.256 1,000 3 1.43 Anisa 2157 CG2 THR 308 3193 4702 4047 -577 -132 - 5 3 8 ATÓM 2158 N SER 309 10.850 -1,591 53217 1,000 24.73 Anisa 2158 N SER 309 2934 2092 4370 93 -574 - 3 9 1 ATÓM 2159 CA SER 309 10.199 -2,897 53230 1,000 5.19 Anisa 2159 CA SER 309 3793 2464 3316 -485 451 - 2 3 0 ATÓM 2160 C SER 309 10.466 -3,691 54.5 L2 1,000 2 4.06 Anisa 2160 C SER 309 2360 2888 3893 302 107 3 5 ATÓM 2161 ABOUT SER 309 11.565 -3,621 55.084 1,000 4.54 Anisa 2161 ABOUT SER 309 3626 2131 7366 -76 -1944 - 3 4 ATÓM 2162 CB SER 309 10.639 -3,700 52012 1,000 6.52 Anisa 2162 CB SER 309 3970 2159 3948 167 580 - 3 6 6 ATÓM 2163 OG SER 309 10.217 -5,039 52.148 1,000 6.34 Anisa 2163 OG SER 309 3198 2207 4604 156 -844 - 2 6 0 ATÓM 2164 N LYS 310 9,494 -4,458 54.961 1,000 2 4.99 Anisa 2164 N LYS 310 3172 2459 3864 160 262 3 6 6 ATÓM 2165 CA LYS 3 10 9.651 -5,339 56.125 1,000 8.38 Anisa 2165 CA LYS 310 4 191 3167 34 27 764 278 2 8 1 ATÓM 2166 C LYS 3 10 9.941 -6,768 55711 1,000 2 6.07

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / G B9SO3860

Anisa 2166 C LYS 3 10 3 37 1 ATÓM 2 167 ABOUT LYS 310 10.150 Anisa 2167 ABOUT LYS 310 5267 ATÓM 2168 CB LYS 310 8.299 Anisa 2168 CB LYS 310 5736 ATÓM 2169 CG LYS 310 8.014 Anisa 2169 CG LYS 310 6395 ATÓM 2170 CD LYS 310 6.798 Anisa 2170 CD LYS 310 9091 ATÓM 2171 CE LYS 310 6.722 Anisa 2171 CE LYS 310 9281 ATÓM 2172 NZ LYS 310 6.088 Anisa 2172 NZ LYS 310 4884 ATÓM 2173 N ALA 311 9896 Anisa 2173 N ALA 311 2190 ATÓM 2174 CA ALA 311 10.360 Anisa 2174 CA ALA 311 3771 ATÓM 2175 C ALA 311 11.909 Anisa 2175 C ALA 311 3907 ATÓM 2176 CB ALA 311 9.619 Anisa 2176 CB ALA 311 2407 ATÓM 2177 OW HOH 501 -6,477 ATÓM 2178 OW HOH 502 -9,349 ATÓM 2179 OW HOH 503 -1,489 ATÓM 2180 OW HOH 504 -10,499 ATÓM 2181 OW HOH 505 -8,612 ATÓM 2182 OW HOH 506 -10,255 ATÓM 2183 OW HOH 507 2.096 ATÓM 2184 OW HOH 508 -0,284 ATÓM 2185 OW HOH 509 -8,525 ATÓM 2186 OW HOH 510 3.165 ATÓM 2187 OW HOH 511 -6,282 ATÓM 2188 OW HOH 512 -6 .826 ATÓM 2189 OW HOH 513 10.510 ATÓM 2190 OW HOH 514 -0,806 ATÓM 2191 OW HOH 515 -1,269 ATÓM 2192 OW HOH 516 14.277 ATÓM 2193 OW HOH 517 -0,123 ATÓM 2194 OW HOH 518 13.131 ATÓM 2195 OW HOH 519 11.009 ATÓM 2196 OW HOH 520 5.789 ATÓM 2197 OW HOH 521 2168 ATÓM 2198 OW HOH 522 8487 ATÓM 2199 OW HOH 523 10.794 ATÓM 2200 OW HOH 524 -11,722 ATÓM 2201 OW HOH 525 1,672 ATÓM 2202 OW HOH 526 9.651 ATÓM 2203 OW HOH 527 28.749 ATÓM 2204 OW HOH 528 15.326 ATÓM 2205 OW HOH 529 26.897 ATÓM 2206 OW HOH 530 13.528 ATÓM 2207 OW HOH 531 25.631 ATÓM 2208 OW HOH 532 18.287 ATÓM 2209 OW HOH 533 12.635 ATÓM 2210 OW HOH 534 10.797 ATÓM 2211 OW HOH 535 10.167 ATÓM 2212 OW HOH 536 23.530 ATÓM 2213 OW HOH 537 23.358 ATÓM 2214 OW HOH 538 25.879 ΛΤΟΜ 2215 OW HOH 539 11.674 ATÓM 22 16 OW HOH 540 18.515

2 6 N 7 3S4 é 1 6 S -290 5 7 - 7. 6 S 4 5 6. 515 1,000 > 3-., 4 8 3056 4400 - 6 p -450 1 0 7 4 -5,367 56858 1,000 7.77 4 695 3921 299 1819 1 8 -4,214 57806 1,000 4 0.55 4716 4295 1525 1524 1 0 1 -4,587 58.649 1. 000 4.24 4224 34 95 1053 2815 5 8 4 -6,109 58.818 1,000 5 9.12 4577 8606 766 -82 2 4 7 8 -6 .563 60089 1,000 5 5.80 5742 10577 287 -948 4 7 9 6 -7,030 54.410 1,000 2.45 2402 3939 10 52 2 6 9 -8,369 53.972 1,000 3 1.89 2594 5753 434 -516 - 4 2 1 -8,459 53833 1,000 2 3.30 2328 2616 1393 -593 1 1 2 -8,665 52.674 1,000 7.94 2878 5329 -355 542-6 6 2 10.237 44.256 1,000 15.66 16.189 51.010 1,000 19:26 3653 34.560 1,000 15.78 18.731 50182 1,000 16:19 16.958 47.640 1,000 17:30 20.839 42.881 1,000 5.19 1.076 32.810 1,000 9.32 4743 41.885 1,000 13.93 18.553 42.416 1,000 2 1.33 2.604 43.488 1,000 4.59 19.386 52.341 1,000 18.98 24.638 46.833 1,000 2 1.77 -4,344 46.092 1,000 2 5.88 16.964 40.372 1,000 16:54 18.855 42.411 1,000 15.76 -5,146 40.175 1,000 15:53 21538 40.640 1,000 17:22 -0,967 51791 1,000 3 1.17 2,875 45.599 1,000 2 0.20 13.543 45.996 1,000 17:36 19767 55.925 1,000 2 0.41 15.960 34.949 1,000 15:40 12.697 29.921 1,000 19.99 19.112 44516 1,000 19.82 -2,081 35.124 1,000 16:29 15.283 32.342 1,000 2 0.37 31.187 52.019 1,000 18:53 11.252 32.041 1,000 19.60 26.984 52035 1,000 19.86 11.592 50.915 1,000 16:17 32409 52682 1,000 19:20 6.835 52185 1,000 18:49 29.035 39.395 1,000 18:09 31.968 45659 1,000 2 0.66 24.890 33.567 1,000 19:12 24.122 58.531 1,000 2 0.39 12.639 35.292 1,000 2.61 28.699 50264 1. 000 19:44 16.559 30.502 1,000 18:57 27.775 40.042 1. 000 2.23

SUBSTITUTE SHEET (RULE 26)

WO 99'33994

PCT'GB98'03860

ATÓM 221 7 OW HOH 541 21233 20:36 33.996 1,000 2 1 4 5 ATÓM 2218 ow HOH 542 22.826 32.643 53.094 1.000 Γ9-. 8 8 ATÓM 2219 OW HOH 543 19 Dec 670 22.387 35.310 1.000 2 0. 0 5 ATÓM 2220 ow HOH 544 -13,591 21996 61.494 1.000 4 9. 9 3 ATÓM 2221 ow HOH 545 21 .295 11.783 55.080 1.000 2 0. 0 4 ATÓM 2222 ow HOH 546 5431 2.533 51.677 1.000 2 8. 1 1 ATÓM 2223 ow HOH 547 17.311 25.489 32.148 1.000 2 4. 3 8 ATÓM 2224 ow HOH 548 17.427 7.744 33.008 1.000 2 0. 7 8 ATÓM 2225 ow HOH 549 11.656 23.874 58.194 1.000 2 3. 3 9 ATÓM 2226 ow HOH 550 8.037 14.987 53.326 1.000 3 3. 5 2 ATÓM 2227 ow HOH 551 1.354 14.574 33.889 1.000 2 1. 0 5 ATÓM 2228 ow HOH 552 11203 20.116 63,686 1,000 2 4. 5 9 ATÓM 2229 ow HOH 553 2. 671 21.240 34.245 1.000 3 4. 5 1 ATÓM 2230 ow HOH 554 6339 19.832 30.751 1.000 2 6. 3 6 ATÓM 2231 ow HOH 555 26.611 24.519 55.570 1.000 2 1. 2 2 ATÓM 2232 ow HOH 556 27.669 17.156 53.039 1.000 2 5. 8 6 ATÓM 2233 ow HOH 557 -14,392 19.977 44.154 1.000 2 5. 0 3 ATÓM 2234 ow HOH 558 14.828 32.652 51.443 1.000 2 5. 2 3 ATÓM 2235 ow HOH 559 17.937 7207 54.915 1.000 2 0. 5 9 ATÓM 2236 ow HOH 560 10.729 -8,875 31.499 1.000 2 4.65 ATÓM 2237 ow HOH 561 6,455 2 .298 42.613 1.000 22nd 7 4 ATÓM 2238 ow HOH 562 13.784 31245 44.166 1.000 2 7. 7 5 ATÓM 2239 ow HOH 563 17.292 33.470 53.556 1.000 2 5. 2 8 ATÓM 2240 ow HOH 564 11.210 1,109 49.697 1.000 2 3.33 ATÓM 2241 ow HOH 565 -11,339 25246 41.370 1.000 2 6. 0 8 ATÓM 2242 ow HOH 566 20.363 -8,375 38.242 1.000 3 0.07 ATÓM 2243 ow HOH 567 3.890 24.604 35.337 1.000 2 5. 8 6 ATÓM 2244 ow HOH 568 5.334 11.875 43.937 1.000 25. 4 5 ATÓM 2245 ow HOH 569 7861 22.385 64.046 1.000 8.98 ATÓM 2246 ow HOH 570 7754 -1,508 30.1348 1.000 2 4. 7 2 ATÓM 2247 ow HOH 571 6297 3.583 28.471 1.000 3 3.06 ATÓM 2248 ow HOH 572 -15,790 28.800 51.855 1.000 3 0. 0 9 ATÓM 2249 ow HOH 573 -5,388 20.310 38.883 1.000 2 3. 64 ATÓM 2250 ow HOH 574 17.657 21.059 29.053 1.000 2 4. 3 1 ATÓM 2251 ow HOH 575 8.763 20.920 66.102 1.000 24.81 ATÓM 2252 ow HOH 576 10.135 27.617 58.357 1.000 2 5. 12 ATÓM 2253 ow HOH 577 7.795 1.060 29.730 1.000 2 9. 00 ATÓM 2254 ow HOH 578 22.601 19.580 61.946 1.000 2 8. 6 6 ATÓM 2255 ow HOH 579 8.859 4744 27.E98 1.000 2 6. 12 ATÓM 2256 ow HOH 580 4937 3. 932 48.882 1.000 2 6. 2 9 ATÓM 2257 ow HOH 581 17.096 5.891 35.057 1.000 2 3. 3 1 ATÓM 2258 ow HOH 582 -16,337 31047 64.719 1.000 54. , 0 1 ATÓM 2259 ow HOH 583 7652 24.826 52.106 1.000 2 7. . 2 3 ATÓM 2260 ow HOH 584 7.174 24.915 29.292 1.000 2 6. . 60 ATÓM 2261 ow HOH 585 23.452 10.614 55.439 1.000 2 6. . 4 2 ATÓM 2262 ow HOH 586 12.640 26.413 58.676 1.000 2 7. . 1 5 ATÓM 2263 ow HOH 587 6204 21.166 62.094 1.000 2 4 . 6 5 ATÓM 2264 ow HOH 588 2.385 0.810 37.616 1.000 1 9. . 9 2 ATÓM 2265 ow HOH 589 32.930 28.236 45.738 1.000 3 8 . 2 9 ATÓM 2266 ow HOH 590 -12,045 28716 45.065 1.000 3 0 . 4 6 ATÓM 2267 ow HOH 591 0219 13.612 36.120 1.000 2 7 . 1 2 ATÓM 2268 ow HOH 592 -2,525 3.881 43.344 1.000 2 6 . 67 ATÓM 2269 ow HOH 593 7533 13,297 48.055 1.000 1 9 . 5 9 ATÓM 2270 ow HOH 594 -1,575 28.355 42.057 1.000 2 5 . 5 3 ATÓM 2271 ow HOH 595 11.209 -1,188 46.425 1.000 2 2 . 1 2 ATÓM 2272 ow HOH 596 5684 -7,000 28.451 1.000 2 7 . 9 7 ATÓM 2273 ow HOH 597 28868 19.406 51.825 1.000 2 7 . 7 2 ATÓM 2274 ow HOH 598 13.432 2.493 57.904 1.000 3 1 . 1 2 ATÓM 2275 ow HOH 599 8. 196 7483 27.148 1.000 2 9 . 9 9 ATÓM 2276 ow HOH 600 20.809 19.088 63.369 1.000 3 6 . 8 6 ATÓM 2277 ow HOH 601 21.352 10.656 34.614 1.000 1 3 0 . 6 0

SUBSTITUTE SHEET (RULE 26)

WO 99 '3399-4

PCT / GB9S'03860

ATÓM 2 2 78 OW HOH 602 2.691 7. 196 ATÓM 2279 ow HO H 603 8.260 26.496 ATÓM 2280 OW HOH 604 22nd 300 13 .959 ATÓM 2281 OW HOH 605 15.689 35.750 ATÓM 2282 ow HOH 606 7219 15.638 ATÓM 2283 ow HOH 607 -3 .237 14.604 ATÓM 2284 ow HOH 608 17.543 10.581 ATÓM 2285 OW HOH 609 -1,899 36.370 ATÓM 2286 ow HOH 610 26.095 14.431 ATÓM 2287 ow HOH 611 27664 13.183 ATÓM 2288 ow HOH 612 4.302 34.604 ATÓM 2289 ow HOH 613 -15,580 27.012 ATÓM 2290 ow HOH 614 1.615 35.544 ATÓM 2291 ow HOH 615 -10,137 34259 ATÓM 2292 ow HOH 616 26.084 6.502 ATÓM 2293 ow HOH 617 -15,962 20.656 ATÓM 2294 ow HOH 618 6.113 29517 ATÓM 2295 ow HOH 619 19.797 4.627 ATÓM 2296 ow HOH 620 -1,748 11.315 ATÓM 2297 ow HOH 621 11,099 34.289 ATÓM 2298 ow HOH 622 28352 14.351 ATÓM 2299 ow HOH 623 -2,826 36.968 ATÓM 2300 ow HOH 624 16.983 9.258 ATÓM 2301 ow HOH 625 16.780 29.213 ATÓM 2302 ow HOH 626 1.632 17.213 ATÓM 2303 ow HOH 627 33536 23.640 ATÓM 2304 ow HOH 628 23.821 6.059 ATÓM 2305 ow HOH 629 3482 2,785 ATÓM 2306 ow HOH 630 20.218 24.803 ATÓM 2307 ow HOH 631 3.366 16.272 ATÓM 2308 ow HOH 632 18.871 11.791 ATÓM 2309 ow HOH 633 4.455 25.782 ATÓM 2310 ow HOH 634 24.721 5202 ATÓM 2311 ow HOH 635 19.623 35.238 ATÓM 2312 ow HOH 636 22.789 26.242 ATÓM 2313 ow HOH 637 7008 -4,809 ATÓM 2314 ow HOH 638 -15,821 18.362 ATÓM 2315 ow HOH 639 -11,847 15.711 ATÓM 2316 OW HOH 640 -1,948 13.411 ATÓM 2317 OW HOH 641 -14,293 21.937 ATÓM 2318 OW HOH 642 18.216 20.839 ATÓM 2319 OW HOH 643 9836 36.288 ATÓM 2320 OW HOH 644 3.510 16.168 ATÓM 2321 ow HOH 645 7571 33.398 ATÓM 2322 OW HOH 646 0.780 21.844 ATÓM 2323 OW HOH 647 21.244 -2,321 ATÓM 2324 OW HOH 648 3.027 25244 ATÓM 2325 OW HOH 649 1.129 25.273 ATÓM 2326 OW HOH 650 14.646 7.560 ATÓM 2327 OW HOH 651 -8,287 26381 ATÓM 2328 ow HOH 652 10.153 23.548 ATÓM 2329 ow HOH 653 28.906 22.258 ATÓM 2330 ow HOH 654 13.568 -4,482 ATÓM 2331 ow HOH 655 -12,635 17.106 ATÓM 2332 ow HOH. 656 2.698 5.770 ATÓM 2333 ow HOH 657 -1,384 7.487 ATÓM 2334 ow HOH 658 3.880 19.246 ATÓM 2335 ow HOH 659 -1,400 31.406 ATÓM 2336 ow HOH 660 11.416 23.260 ATÓM 23 37 ow HOH 661 15.994 14.673 ATÓM 23 38 ow HOH 662 28.572 21. 242

30.899 34.551 31. 378 48,870 30,914 47,092 33,561 44,261 43,803 41,954 49,981

46.728 50.347 49.033 57.657 46.340 40.143 51.313 48.716 44.259 37.877 57.149 29.962

38.384 33.689 45.028 50.174 46.751 60.918 30.698

31.384 58.823 40.319 43.466 60.797 54.039 42.559 52.841 35.401 42.145 66.863 48.178 66.253 41.687

36.729 35.579 69.907

66.516 60.327 37.998 67.703 38.969

31.517 55.637 50.702 46.512 31.498 64.001 65.229 25.680 53.423. 000. 000

1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1. 000

5.41 3 ^ 5. * 1

32.53

2.17

7.80

0.96

23:51

32.64

19:19

6:48

4.70

42.45

3.78

23.94

39.32

5.94

9:43

7.15

1.83

27.15

41.48

32.75

32.82

27.96

23:17

41.91

34.22

7.9

50.12

1:50

0.78

2.14

40.13

50.48

26.58

33.89

9.61

25.21

30.41

27.58

31.23

44.21

3.82

7.96

1.71

2:40

6.84

35.42

46.42

29.17

31.50

2.66

6.94

6.85

29.05

36.52

1:50

56.62

2.69

6:46

6.9

SUBSTTLUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S'O386O

ATÓM 2339 OW HOH 6 6 3 19.354 - 87 - 0465 27.273 1,000 4 4.56 ATÓM 2340 OW HOH ó 6 4 24. 969 27.026 3S. 838 1,000 3 * 5- <1 ATÓM 2341 OW HOH 6 6 5 24294 7488 55.914 1,000 3 2.97 ATÓM 2342 OW HOH 6 6 6 19.540 7. 882 31.173 1: 000 3 0.04 ATÓM 2343 OW HOH 667 -9,236 32. 988 57.241 1. 000 3 9 2 0 ATÓM 2344 ow HOH 668 2. 098 18.351 67496 1,000 3 8. S 3 ATÓM 2345 OW HOH 669 11.390 3245 56.270 1,000 3 7.56 ATÓM 2346 ow HOH 670 -21,413 24.449 52026 1,000 4 4. at 6 ATÓM 2347 ow HOH 671 -14,575 19.220 55 240 1,000 3 0.91 ATÓM 2348 ow HOH 672 32.112 25958 43 051 1,000 3 3.34 ATÓM 2349 ow HOH 673 -15,050 31.151 53.232 1,000 3 4.71 ATÓM 2350 ow HOH 674 2.941 -1,607 30.245 1,000 3 4.63 ATÓM 2351 ow HOH 675 26.951 14.544 34.757 1,000 9.17 ATÓM 2352 ow HOH 676 14.707 30.669 39.386 1,000 3 0.55 ATÓM 2353 ow HOH 677 5203 18.009 68080 1,000 4 3.41 ATÓM 2354 ow HOH 678 14.151 7.965 26.591 1,000 3 8.80 ATÓM 2355 ow HOH 679 24.470 24.261 41.443 1,000 3 1.28 ATÓM 2356 ow HOH 680 17.540 2.410 28.478 1,000 3 4.31 ATÓM 2357 ow HOH 681 25.992 20.593 34326 1,000 9.66 ATÓM 2358 ow HOH 682 13.802 35.357 44.421 1,000 3 4.06 ATÓM 2359 ow HOH 683 1,087 2.355 45.456 1,000 5.39 ATÓM 2360 ow HOH 684 22.443 34538 42.053 1,000 3 3.55 ATÓM 2361 ow HOH 685 4419 4.720 27.356 1,000 8.02 ATÓM 2362 ow HOH 686 -15,830 34.507 51.377 1,000 5 0.63 ATÓM 2363 ow HOH 687 -15,217 29.490 48.387 1,000 3.54 ATÓM 2364 ow HOH 688 36.808 21.183 46.206 1,000 44.97 ATÓM 2365 ow HOH 689 3,756 1,312 29.272 1,000 5.16 ATÓM 2366 ow HOH 690 18.802 13.646 27.901 1,000 3 0.08 ATÓM 2367 ow HOH 691 6997 17.521 29.313 1,000 4 7.70 ATÓM 2368 ow HOH 692 13,725 16.327 69105 1,000 3 6.97 ATÓM 2369 ow HOH 693 22.369 22.161 60503 1,000 4 4.09 ATÓM 2370 ow HOH 694 -5,429 31.620 42.219 1,000 3 3.40 ATÓM 2371 ow HOH 695 19.351 23.082 30.744 1,000 4.21 ATÓM 2372 ow HOH 696 6.897 22414 29.276 1,000 6.59 ATÓM 2373 ow HOH 697 28.700 7809 57.304 1,000 38.35 ATÓM 2374 ow HOH 698 3.224 0679 39.819 1,000 4.13 ATÓM 2375 ow HOH 699 -4,634 33717 62593 1,000 2.26 ATÓM 2376 ow HOH 700 32.423 17.018 43.200 1,000 4 3.20 ATÓM 2377 ow HOH 701 12.119 25.228 68342 1,000 3 9.95 ATÓM 2378 ow HOH 702 9307 16.477 28976 1,000 3 1.75 ATÓM 2379 ow HOH 703 -11,313 34067 46.117 1,000 4 9.40 ATÓM 2380 ow HOH 704 7.774 31.390 65371 1,000 3 9.12 ATÓM 2381 ow HOH 705 24.764 7.530 36.802 1,000 8.55 ATÓM 2382 ow HOH 706 -22,095 25.669 59047 1,000 6.71 ATÓM 2383 ow HOH 707 14.509 9.840 68854 1,000 5 0.38 ATÓM 2384 ow HOH 708 -10,129 28722 42036 1,000 8.92 ATÓM 2385 ow HOH 709 29.011 34.910 48.390 1,000 5.29 ATÓM 2386 ow HOH 710 15.822 31.612 42021 1,000 3 3.61 ATÓM 2387 ow HOH 711 -1,996 17.676 33.645 1,000 4 9.57 ATÓM 2388 ow HOH 712 10.216 17.748 26.015 1,000 4 1.04 ATÓM 2389 ow HOH 713 23.535 29642 37.371 1,000 4 3.47 ATÓM 2390 ow HOH 714 20.488 -7,214 35599 1,000 4 5.99 ATÓM 2391 ow HOH 715 11.411 10.149 25.031 1,000 4 1.63 ATÓM 2392 ow HOH 716 19329 -4,258 34.139 1,000 4 2.50 ATÓM 2393 ow HOH 717 13.688 26.799 66321 1,000 4 3.74 ATÓM 2394 ow HOH 718 -10,751 33064 54747 1,000 4 0.47 ATÓM 2395 ow HOH 719 13.800 18258 70756 1,000 4.54 ATÓM 2 396 ow HOH 720 17.151 5815 28.003 1,000 4 0.80 ATÓM 2397 ow HOH 721 0.000 0.000 36.691 0.330 7.42 ATÓM 2398 ow HOH 722 0.000 0.000 41559 0.330 7.77 ATÓM 2399 ow HOH 723 15.314 7.549 28.791 1,000 6.24

SUBSTTTUTE SHEET (RULE 26)

WO 99/3994

PCT / GB98 / 03860

ATÓM 2400 OW HOH 724 -1,663 19.944 39.196 1.000 ^ 3.87 ATÓM 2401 OW HOH 725 19.289 24.195 33.321 1,000 32.28 ATÓM 2402 OW HOH 726 0.000 0.000 31.798 RMB330 50.38 ATÓM 2403 OW HOH 727 -1,223 38.165 59.229 1,000 31.24 ATÓM 2,404 OW HOH 728 22.035 38254 45.742 1,000 48.21 ATÓM 2405 OW HOH 729 28.388 16.248 63044 1,000 31.59 ATÓM 2406 OW HOH 730 0.000 0.000 45.995 0.330 36.14 ATÓM 2407 OW HOH 731 2984 29.007 40.091 1,000 36.08 ATÓM 2408 OW HOH 732 5297 15.835 27.318 1,000 41.53 ATÓM 2409 OW HOH 733 17.347 10.778 27.373 1,000 35.27 ATÓM 2410 OW HOH 734 29.417 14.607 53.127 1,000 40.12 ATÓM 2411 OW HOH 735 4.222 -8,636 27.012 1,000 35.22 ATÓM 2412 OW HOH 736 -9,949 17.712 62813 1,000 34.43 ATÓM 2413 OW HOH 737 13.960 -10,203 55259 1,000 31.79 ATÓM 2414 OW HOH 738 11.831 -1,522 49.308 1,000 25.22 ATÓM 2415 OW HOH 739 2896 4247 29.596 1,000 38.64 ATÓM 2416 OW HOH 740 10.959 13.759 25.528 1,000 61.86 ATÓM 2417 OW HOH 741 0.864 17.227 30.557 1,000 50.71 ATÓM 2418 OW HOH 742 31.755 18.949 52065 1,000 40.48 ATÓM 2419 OW HOH 743 21.678 -0,485 28.218 1,000 43.23 ATÓM 2420 OW HOH 744 10583 16.397 75211 1,000 45.04 ATÓM 2421 OW HOH 745 7.480 7.996 78287 1,000 57.64 ATÓM 2422 OW HOH 746 24.067 35.122 40.297 1,000 41.95 ATÓM 2423 OW HOH 747 7.804 10.269 78332 1,000 49.63 ATÓM 2424 OW HOH 748 22.131 40.645 45.806 1,000 49.69 ATÓM 2425th OW HOH 749 14.850 -4,647 33.872 1,000 42.88 ATÓM 2426 OW HOH 750 -12,930 32.504 55.211 1,000 37.15 ATÓM 2427 OW HOH 751 -4,832 35.986 43.333 1,000 44.39 ATÓM 2428 OW HOH 752 19.834 33.566 56.449 1,000 31.56 ATÓM 2429 OW HOH 753 3363 22.310 29.844 1,000 42.02 ATÓM 2430 OW HOH 754 25.594 4.030 34.174 1,000 51.90 ATÓM 2431 OW HOH 755 28.036 35.859 46.448 1,000 39.50 ATÓM 2432 OW HOH 756 -12,951 16,294 61787 1,000 40.94 ATÓM 2433 OW HOH 757 -10,870 26452 38.737 1,000 44.85 ATÓM 2434 OW HOH 758 13.216 12.896 70729 1,000 63.42 ATÓM 2435 OW HOH 759 -0,403 21.161 74.990 1,000 38.96 ATÓM 2436 OW HOH 760 -7,025 32.526 64316 1,000 39.64 ATÓM 2437 OW HOH 761 -15,459 19.739 58.090 1,000 40.84 ATÓM 2438 OW HOH 762 -4,964 36577 59.068 1,000 48.64 ATÓM 2439 OW HOH 763 26.807 35717 50.036 1,000 43.54 ATÓM 2440 OW HOH 764 19.542 7.083 65538 1,000 41.41 ATÓM 2441 OW HOH 765 3,709 35837 42.709 1,000 33.78 ATÓM 2442 OW HOH 766 0.431 33688 40.172 1,000 36.91 ATÓM 2443 OW HOH 767 18.620 5064 64617 1,000 45.76 ATÓM 2444 OW HOH 768 35.526 19.792 41.322 1,000 52.54 ATÓM 2445 OW HOH 769 19.671 7.789 67717 1,000 43.44 ATÓM 2446 OW HOH 770 3.562 12.048 26.149 1,000 40.08 ATÓM 2447 OW HOH 771 20.245 35637 53927 1,000 52.16 ATÓM 2448 OW HOH 772 -20,588 25.640 61573 1,000 58.60 ATÓM 2449 OW HOH 773 1.556 37.342 52.171 1,000 36.23 ATÓM 2450 OW HOH 774 8.340 0668 49382 1.000107.24 ATÓM 2451 OW HOH 775 27.160 2.372 34.466 1,000 59.84 ATÓM 2452 OW HOH 776 6.575 19.271 25.545 1,000 36.68

SUBSTTTUTE SHEET (RULE 26) \ WO 99/33994

PCT / GU9S / 03860

ATÓM ATÓM 2453 2454 ow ON HOH HOH 777 778 -17.605 29.205 62661 24.722 1.0 00 ^ -56.7 1.000 61.34 7.616 6. 902 ATÓM 2455 OW HOH 779 19.749 10.700 68006 -1.000 65.22 ATÓM 2456 W HOH 780 7.281 -5,270 50.090 1.000 50.00 ATÓM 2457 W HOH 781 -6 .809 28.483 40.515 1.000 50.00 ATÓM 2458 W HOH 782 9.990 17.263 38.636 1.000 50.00 ATÓM 2459 w HOH 783 5767 -2,331 28.939 1.000 50.00 ATÓM 2460 w HOH 784 11.694 -0.118 24.984 1.000 50.00 ATÓM 2461 w HOH 785 24.442 7,952 47.994 1.000 50.00 ATÓM 2462 w HOH 786 14.251 36.889 46.491 1.000 50.00 ATÓM 2463 w HOH 787 5.759 26.477 33.851 1.000 50.00 ATÓM 2464 w HOH 788 -11,816 22.606 40.795 1.000 50.00 ATÓM 2465 w HOH 789 -2,531 5579 <5.829 1.000 50.00 ATÓM 2466 w HOH 790 -13,002 32.034 46.612 1.000 50.00 ATÓM 2467 w HOH 791 2.230 3555 48.985 1.000 50.00 ATÓM 2468 w HOH 792 9.397 13.464 28, 121 1.000 50.00 ATÓM 2469 w HOH 793 28257 10.442 42.781 1.000 50.00 ATÓM 2470 w HOH 794 4,652 17.944 59.241 1.000 50.00 ATÓM 2471 w HOH 795 5977 15287 79554 1.000 50.00 ATÓM 2472 w HOH 796 30.501 11.852 47616 1.000 50.00 ATÓM 2473 w HOH 797 5.625 14.258 54.367 1.000 50.00 ATÓM 2474 w HOH 798 23.942 20228 33277 1.000 50.00 ATÓM 2475 w HOH 799 10.164 14642 53.997 1.000 50.00 ATÓM 2476 w HOH 800 7.807 31943 52.999 1.000 50.00 ATÓM 2477 w HOH 801 23.377 9.361 34.817 1.000 50.00 ATÓM 2478 w HOH 802 21.193 9.722 32.004 1.000 50.00 ATÓM 2479 w HOH 803 34.928 14.644 46.038 1.000 50.00 ATÓM 2480 w HOH 804 29073 16.684 34. .445 1.000 50.00 ATÓM 2481 w HOH 805 7008 -2,049 51.872 1.000 50.00 ATÓM 2482 w HOH 806 25.363 7.860 45.531 1.000 50.00 ATÓM 2483 w HOH 807 30.704 8.207 55.971 1.000 50.00 ATÓM 2484 w HOH 808 33.072 24,900 40.599 1.000 50.00 ATÓM 2485 w HOH 809 -15,577 19.225 63152 1.000 50.00 ATÓM 2486 w HOH 810 6072 18.137 23603 1.000 50.00 ATÓM 2487 w HOH 811 -7,214 39.940 55.639 1.000 50.00 ATÓM 2488 w HOH 812 5509 18.517 74919 1.000 50.00 ATÓM 2489 w HOH 813 33845 9.908 56.672 1.000 50.00 ATÓM 2490 w HOH 814 0421 35.779 42.931 1.000 50.00 ATÓM 2491 w HOH 815 35.282 21.705 48.656 1.000 50.00 ATÓM 2492 w HOH 816 39.344 22.173 46.871 1.000 50.00 ATÓM 2493 w HOH 817 -5,192 39.820 60056 1.000 50.00 ATÓM 2494 w HOH 818 30.199 13.039 33 .383 1.000 50.00 ATÓM 2495 w HOH 819 -4,860 36454 61731 1.000 50.00 ATÓM 2496 w HOH 820 -14,599 17.407 58.382 1.000 50.00 ATÓM 2497 w HOH 821 1.340 -0,111 41711 0.500 50.00 ATÓM 2498 w HOH 822 34.512 23.218 52.108 1.000 50.00 ATÓM 2499 w HOH 823 32.136 12.571 52.190 1.000 50.00 ATÓM 2500 w HOH 824 13.525 -6,549 29838 1.000 50.00 ATÓM 2501 w HOH 825 6072 -4,141 27.534 1.000 50.00

SUBSTITUTE SHEET (RULE 26)

WO 99CU994

PCT / GB98O3860

- 90 STRUCTURE B

ATÓM 1 CB MET 1 31.030 11.882 57.066 1. 000 5 0. 9 ó Anisa 1 CB MET 1 5663 3892 9809 1113 -22 17 - 5 5 4 ATÓM 2 CG MET 1 30.206 12.690 56086 1. 000 5 1.63 Anisa 2 CG MET 1 6595 3775 9246 691 -1890 1 6 9 ATÓM 3 SD MET 1 28.694 11.848 55.559 1,000 4 0.50 Anisa 3 SD MET 1 7003 3962 4424 833 -1535 -460 ATÓM 4 CE MET 1 27852 11.584 57.120 1,000 4 5.32 Anisa 4 CE MET 1 8632 3912 4677 -239 -653 - 1 7 0 3 ATÓM 5 C MET 1 31.587 13.367 58.999 1,000 5 2.14 Anisa 5 C MET 1 6204 4752 8854 287 -2128 - 6 3 ATÓM 6 ABOUT MET 1 31.239 12.847 60058 1,000 52.92 Anisa 6 ABOUT MET 1 7381 5242 7483 1417 -4224 519 ATÓM 7 N MET 1 33.170 11.646 58.275 1,000 5 7.78 Anisa 7 N MET 1 4533 6034 11388 34 -1912-8 1 1 ATÓM 8 ' CA MET 1 32156 12.587 57819 1,000 5 4.62 Anisa 8 CA MET 1 6441 4752 9560 137 -2012 - 6 1 6 ATÓM 9 N ASP 2 31.485 14.679 58792 1,000 4 3.52 Anisa 9 N ASP 2 3460 4866 8210 474 -2350 4 7 ATÓM 10 CA ASP 2 30759 15.471 59.796 1,000 4 1.69 Anisa 10 CA ASP 2 4439 4678 6722 -309 -2603 - 2 1 ATÓM 11 CB ASP 2 31.206 16.912 59.644 1,000 7.89 Anisa 11 CB ASP 2 3805 4768 5822 -304 -3473 266 ATÓM 12 CG ASP 2 30.219 17.958 60.121 1,000 9.59 Anisa 12 CG ASP 2 4511 4616 5916 15 -3218 589 ATÓM 13 ODL ASP 2 29.325 17.637 60.933 1,000 4 5.10 Anisa 13 ODL ASP 2 5866 4689 6581 -553 - 1950 - 6 2 5 ATÓM 14 OD2 ASP 2 30.363 19.121 59.663 1,000 42.05 Anisa 14 OD2 ASP 2 5994 4341 5643 -465 -3788 145 ATÓM 15 C ASP 2 29.275 15.213 59.556 1,000 3 3.84 Anisa 15 No. ASP 2 4131 3634 5094 -59 -1683 - 1 2 2 ATÓM 16 ABOUT ASP 2 28.901 15.176 58.379 1,000 9.25 Anisa 16 ABOUT ASP 2 2232 4393 4489 658 -390- 6 1 5 ATÓM 17 N THR 3 28467 15.029 60597 1,000 9.41 Anisa 17 N THR 3 4731 2636 3807 907 - 2076 - 2 8 4 ATÓM 18 CA THR 3 27.046 14.764 60421 1,000 8.55 Anisa 18 CA THR 3 4602 2494 3753 597 -1006 - 3 0 0 ATÓM 19 CB THR 3 26447 13.762 61414 1,000 6.51 Anisa 19 CB THR 3 7170 2209 4495 -791 -1995 5 2 ATÓM 20 OG1 THR 3 26.629 14.220 62758 1,000 4 2.45 Anisa 20 OG1 THR 3 9519 2620 3989 -920 -1251 383 ATÓM 21 CG2 THR 3 27.153 12.412 61315 1,000 5 0.26 Anisa 21 CG2 THR 3 9604 1863 7630 -602 -733- 3 3 3 ATÓM 22 C THR 3 26.240 16.061 60553 1,000 2 9.01 Anisa 22 C THR 3 4535 2548 3939 738 -1079 9 9 ATÓM 23 ABOUT THR 3 25.041 16.044 60827 1,000 3 5.82 Anisa 23 ABOUT THR 3 5149 2485 5976 390 525 - 1 2 4 6 ATÓM 24 N THR 4 26928 17.181 60.332 1,000 2 4.98 Anisa 24 N THR 4 3874 2456 3162 542 -2040-9 8 6 ATÓM 25 CA THR 4 26.214 18.465 60327 1,000 2 3.97 Anisa 25 CA THR 4 3437 2426 3244 344 -1563 - 3 7 ATÓM 26 CB THR 4 27.183 19.650 60408 1,000 6.77 Anisa 26 CB THR 4 2636 2429 5105 651 -988-9 2 3 ATÓM 27 OG1 THR 4 28.050 19.484 61551 1,000 3 2.62 Anisa 27 OG1 THR 4 3398 2812 6184 195 -2081 - 1 2 3 4 ATÓM 28 CG2 THR 4 26.429 20942 60663 1,000 2 6.40 Anisa 28 CG2 THR 4 2373 2692 4967 533 -573 - 1 5 6 0 ATÓM 29 C THR 4 25. 325 18.577 59.097 1,000 2 1.64 AIJISOU 29 C THR 4 3090 2760 2374 368 -750-2 0 ATÓM 30 ABOUT THR 4 25.738 1 8. 264 57.980 1. 000 2 1 5 7 AfIISOU 3 0 ABOUT THP. 4 2 668 2629 2902 246 - 5 6 G - C 5 'S ATÓM 3 1 H VAL 5 24.104 19.049 59.340 1. 000 15.88

SUBSTTTUTE SHEET (RULE 26)

WO 99.33994

PCT / GB9S'03860

Anisa 3 1 N V A L 5 2505 2 C 2 1 1508 -613 -630 - 1 é 2 ATÓM 32 C Λ VAL 5 23.211  9.3S5 58.211 1. 000Ί- *! »8 0 Anisa 32 C A VAL 5 2463 1893 1266 -594 -473-8 7 ATÓM 33 CB VAL 5 21. 742 19.402 53.606 '1.0 00 9.16 Anisa 33 CB VAL 5 2476 1881 1757 -412 -406 5 0 2 ATÓM 34 CG1 VAL 5 20.855 29.846 57.447 1,000 14.91 Anisa 34 CG1 VAL 5 2468 1859 13 3 7 9 -102 1 9 6 ATÓM 35 CG2 VAL 5 21.310 17.994 59074 1,000 2 1.15 Anisa 3 5 CG2 VAL 5 3015 2345 2 67 7 -700 -41S 119 8 ATÓM 3 ó C VAL 5 23639 20.762 57694 1,000 17.70 Anisa 36 C VAL 5 2893 2085 17 49 -1137 -713 103 ATÓM 37 ABOUT VAL 5 23.532 21.759 58419 1,000 17:35 Anisa 37 ABOUT VAL 5 2566 1978 2C50 -698 -650 105 ATÓM 38 N PRO 6 24.150 20.845 56.479 1,000 13:23 Anisa 38 N PRO 6 1334 1597 2097 -162 -668 409 ATÓM 39 CD PRO 6 24.302 19.770 55.484 1,000 15:56 Anisa 39 CD PRO 6 1887 1850 2176 -309 -383 277 ATÓM 40 C A PRO 6 24.667 22.137 56.005 1,000 14:49 Anisa 40 CA PRO 6 1332 1740 2432 -218 - 5 3 6 5 2 2 ATÓM 41 CB PRO 6 25,571 21.722 54.847 1,000 18:21 Anisa 41 CB PRO 6 2294 1740 2886 -224 130 434 ATÓM 42 CG PRO 6 25132 20.378 54.409 1,000 2 0.37 Anisa 42 CG PRO 6 2708 2632 23 99 -1,078 38-61 ATÓM 43 C PRO 6 23.576 23.091 55.510 1,000 14:59 Anisa 43 C PRO 6 1388 1712 2443 -406 -786 698 ATÓM 44 ABOUT PRO 6 22.408 22.743 55.295 1,000 13.6 Anisa 44 ABOUT PRO 6 1298 1547 2118 -283 -596 1 5 ATÓM 45 N THR 7 24.048 24.326 55.313 1,000 14:56 Anisa 45 N THR 7 1393 1678 2463 -380 -565 587 ATÓM 46 CA THR 7 23.288 25.428 54.771 1,000 13:28 Anisa 46 CA THR 7 1463 1584 1998 -469 -734 440 ATÓM 47 CB THR 7 23.121 26.572 55799 1,000 14:44 Anisa 47 CB THR 7 1927 1652 1905 -348 -1257 329 ATÓM 48 OG1 THR 7 22.454 26.102 56.998 1,000 18:44 Anisa 48 OG1 THR 7 3136 2013 1858 -333 -829 176 ATÓM 49 CG2 THR 7 22.290 27.719 55.261 1,000 14.98 Anisa 49 CG2 THR 7 1390 1788 2513 -213 -727 412 ATÓM 50 C THR 7 23.973 26.005 53.539 1,000 14.62 Anisa 50 C THR 7 1144 2200 2212 -355 -693 704 ATÓM 51 ABOUT THR 7 25.192 26.257 53.600 1,000 17:21 Anisa 51 ABOUT THR 7 1284 2515 2738 -641 -840 975 ATÓM 52 N PHE 8 23.211 26.222 52.472 1,000 12:32 Anisa 52 N PHE 8 1165 1596 1919 -314 -534 370 ATÓM 53 CA PHE 8 23.692 26869 51283 1,000 13:31 Anisa 53 CA PHE 8 1554 1531 1971 -60 -295 343 ATÓM 54 CB PHE 8 23.724 25.933 50.067 1,000 13.71 Anisa 54 CB PHE 8 1479 1705 2025 -136 -232 234 ATÓM 55 CG PHE 8 24635 24.746 50.2S8 1,000 13.68 Anisa 55 CG PHE 8 1225 1716 2257 -185 8 15 5 ATÓM 56 CD1 PHE 8 24.147 23.503 50.528 1,000 14:10 Anisa 56 CD1 PHE 8 1317 1710 23 2'9 -93 231 221 ATÓM 57 CD2 PHE 8 26.006 24.882 50079 1,000 17:52 Anisa 57 CD2 PHE 8 1239 2282 3134 -234 -56 917 ATÓM 58 CE1 PHE 8 24.984 22.420 50. (312 1,000 15:39 Anisa 58 CE1 PHE 8 1473 1878 2 4 97 -11 242 481 ATÓM 59 CE2 PHE 8 26.840 23.807 50.271 1,000 17.73 Anisa 59 CE2 PHE 8 1179 2259 33 01 -157 -143 423 ATÓM 60 CZ PHE 8 26.348 22567 50.654 1,000 17:12 Anisa 60 CZ PHE 8 1310 2437 27 5 '» 24 -382,978 ATÓM 61 C PHE 8 22.821 28.073 50.909 1. 000 12.76 Anisa 61 C PHE 8 1401 1513 1935 -164 -145 442

SUBSTTTUTE SHEET (RULE 26) \ WO 99 / 3399-4

PCT'GBOS'03860

ATÓM 6 2 0 PHE WITH 21. 602 - 92 - 28.033 51.079 1. 000 L-3. 1 S Anisa 62 0 PHE WITH 1392 1295 2322 -2 5 6 * T0 * 0 3 6 4 ATÓM 63 N SER Q 23 .478 29.096 50394 1. 000 1 3.0 3 Anisa 63 N SER Q 1722 1636 1593 -566 -601 4 9 0 ATÓM 64 C A SER 9 22.861 30224 49.718 1. 000 1 2.5 Anisa 64 C A SER 9 1591 1468 1708 -392 -437 3 1 5 ATÓM 65 CB SER 9 23.743 31.472 49. 761 1.000 1 5.4 1 Anisa 65 CB SER 9 2385 1833 1637 -915 -1057 783 ATÓM 66 OG SER 9 23.138 32.539 49.007 1,000 1 7.9 9 Anisa 66 OG SER 9 2504 1721 2611 -718 -999 9 2 5 ATÓM 67 C SER 9 22nd 520 29.868 48.276 1,000 1 2.7 2 Anisa 67 C SER 9 2040 1187 1606 -411 -576 4 7 7 ATÓM 68 0 SER 9 23.397 29.495 47. 478 1.000 1 6.1 8 Anisa 68 0 SER 9 2265 2053 1830 -465 -381 7 ATÓM 69 N LEU 10 21.229 29982 47.968 1 - 000 1 4.1 9 Anisa 69 N LEU 10 2154 1488 1750 -301 -699 1 7 5 ATÓM 70 C A LEU 10 20798 29.714 46.596 1,000 1 4.62 Anisa 70 C A LEU 10 2243 1579 1734 -184 -784 ATÓM 71 CB LEU 10 19.291 29.883 46436 1,000 1 4.7 2 Anisa 71 CB LEU 10 2222 1714 1657 -142 -657-1 ATÓM 72 CG LEU 10 18.693 29.633 45.050 1,000 1 4.1 0 Anisa 72 CG LEU 10 2087 1557 1713 -702 -695 ATÓM 73 CD1 LEU 10 18.986 28214 44.582 1.000 1 6.2 3 Anisa 73 CD1 LEU 10 2994 1578 1595 -554 -1133 8 7 ATÓM 74 CD2 LEU 10 17.198 29.913 44.997 1,000 2 1 .82 Anisa 74 CD2 LEU 10 2180 2904 3206 -421 -1151-518 ATÓM 75 C LEU 10 21.531 30639 45.626 1,000 1 5.87 Anisa 75 C LEU 10 2449 1785 1796 -491 -844 ATÓM 76 0 LEU 10 21.962 30.199 44.553 1.000 1 6.3 3 Anisa 76 0 LEU 10 2607 1816 1780 -601 -829 2 6 7 ATÓM 77 -N ALA 11 21669 31.917 45.986 1,000 1 7.17 Anisa 77 N ALA 11 2521 1889 2115 -608 -548 1 3 9 ATÓM 78 CA ALA 11 22.335 32.912 45.129 1.000 16.56 Anisa 78 CA ALA 11 2377 1884 2029 -732 -1033 302 ATÓM 79 CB ALA 11 22.199 34259 45.805 1.000 2 0.0 5 Anisa 79 CB ALA 11 3210 1877 2529 -670 -673 2 5 9 ATÓM 80 C ALA 11 23.786 32.535 44831 1.000 1 6.3 3 Anisa 80 C ALA 11 2319 2255 1629 -754 -988 ATÓM 81 0 ALA 11 24.260 32587 43.677 1.000 19.66 Anisa 81 0 ALA 11 3115 2559 1795 -948 -560 6 1 9 ATÓM 82 N GLU 12 24.558 32.085 45.810 1.00017.28 Anisa 82 N GLU 12 2686 1994 1884 -454 -1087 390 ATÓM 83 CA GLU 12 25.931 31.654 45.752 1.000 16.34 Anisa 83 CA GLU 12 2703 1674 1831 -474 -889 1 0 3 3 ATÓM 84 CB GLU 12 26527 31.477 47158 1.000 16.09 Anisa 84 CB GLU 12 2440 1867 1808 -770 -820 1 0 5 8 ATÓM 85 CG GLU 12 26.633 32.802 47.915 1.000 18.90 Anisa 85 CG GLU 12 2717 2127 2335 -1216 -1090 788 ATÓM 86 CD GLU 12 27.115 32.657 49.342 1.000 21.17 Anisa 86 CD GLU 12 3300 2547 2198 -1182 -1053 724 ATÓM 87 OEL GLU 12 27.538 31558 49.756 1.000 2 2. 07 Anisa 87 OEL GLU 12 2722 3014 2650 -720 -1365 797 ATÓM 88 0E2 GLU 12 27.068 33.679 50.059 1.000 29.26 Anisa 88 OE2 GLU 12 5764 2634 2722 -1279 -1848 ATÓM 89 C GLU 12 25.997 30.402 44.882 1. 000 7 7.1 6 Anisa 89 C GLU 12 2044 2319 2158 -624 -716 4 8 1 ATÓM 90 0 GLU 12 26879 30.317 44.032 1,000 1 8-8 8 Anisa 90 0 GLU 12 3200 2388 1583 -1004 -306 899 ATÓM 91 you LEU 13 25.083 29.441 45.049 1. 000 1 7.3 2 Anisa 91 tJ LEU 1 3 2176 2300 2104 -659 -386 9 ATÓM 92 C A LEU 1 3 25.082 28 .252 44.189 1.000 14.00

SUBSTTRTTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ANISOU 92 C Ä LEU 1 3 1734 -93 1873 .7 13 -140 -17049c ATÓM 93 cs LEU 1 3 24.003 27.248 44.620 1. 0 00-5.5 ». 3 7 Anisa 93 C D LEU 1 3 2205 1838 17 95 -375 -149 465 ATÓM 94 CG LEU 13 24.154 26.554 -5,967 i. 000 14:52 Anisa 94 CG LEU 1 3 1913 1803 1799 -280 -204 442 ATÓM 95 CD1 LEU 13 22934 25. 680 46.193 1,000 15:15 Anisa 95 CD1 LEU 13 2174 1817 1766 -433 165 175 ATÓM 96 CD2 LEU 1 3 25.411 25.690 46.067 1,000 17:54 Anisa 96 CD2 LEU 13 2119 2043 2502 -38 -419 2 7 Q ATÓM 97 C LEU 13 24.876 28.626 42.725 1,000 16:54 Anisa 97 C LEU 13 2510 2062 1710 -222 -93 565 ATÓM 98 ABOUT LEU 13 25.548 28.122 41.821 1,000 18:28 Anisa 98 ABOUT LEU 13 2685 2514 1748 -687 74 2 5 9 ATÓM 99 N GLN 14 23.945 29.534 42.472 1,000 16.86 Anisa 99 N GLN 14 1970 2337 2100 -557 -683 838 ATÓM 100 C A GLN 14 23.657 30015 4 L.132 1,000 18.63 Anisa 100 C A GLN 14 2761 2,404 1915 -610 -802 568 ATÓM 101 CB GLN 14 22.421 30.923 41.130 1,000 19:39 Anisa 101 CB GLN 14 3166 2176 2 02 5 -392 -918 977 ATÓM 102 CG GLN 14 21.108 30.250 41.460 1,000 19:00 Anisa 102 CG GLN 14 2879 2383 19 57 -209 -725 460 ATÓM 103 CD GLN 14 19.974 31.227 41.766 1,000 18.83 Anisa 103 CD GLN 14 3139 2118 18 97 -6 -1229 494 ATÓM 104 OE1 GLN 14 20.177 32.317 42 .314 1,000 6.10 Anisa 104 OE1 GLN 14 3928 2407 35 82 -98 - 1172 - 2 4 1 ATÓM 105 NE2 GLN 14 18.745 30823 41.411 1,000 2 0.94 Anisa 105 NE2 GLN 14 2900 2716 2340 -149 -840 454 ATÓM 106 C GLN 14 24.804 30.812 40.525 1,000 2 0.40 Anisa 106 C GLN 14 3226 2458 2065 -795 -712 937 ATÓM 107 ABOUT GLN 14 24.812 30951 39.311 1,000 3 0.48 Anisa 107 0 GLN 14 5089 4340 2152 -2,337 -899 1 2 1 1 ATÓM 108 N GLN 15 25734 31.309 41.329 1,000 2 0.35 Anisa 108 N GLN 15 3252 2452 2030 -1067 -240 497 ATÓM 109 C A GLN 15 26.909 32.041 40884 1,000 2 1.88 Anisa 109 CA GLN 15 3184 3230 1901 -1152 -299 788 ATÓM 110 CB GLN 15 27.288 33.100 41.920 1,000 2.20 Anisa 110 CB GLN 15 2720 3162 25 51 -1131 -770 691 ATÓM 111 CG GLN 15 26.450 34.358 41.954 1,000 2 5.73 Anisa 111 CG GLN 15 4496 2735 2545 -821 -232 1 2 6 9 ATÓM 112 CD GLN 15 26.325 35.021 43 .306 1,000 3 5.76 Anisa 112 CD GLN 15 6010 3945 3 631 -643 -229 - 1 3 ATÓM 113 OE1 GLN 15 27.145 34.884 44 .225 1,000 9.13 Anisa 113 OE1 GLN 15 8425 5866 4378 -2,857 -2197 - 5 7 4 ATÓM 114 NE2 GLN 15 25.255 35812 43489 1,000 5 1.85 Anisa 114 NE2 GLN 15 7190 5567 6945 62 3066 ATÓM 115 C GLN 15 28069 31079 40.625 1,000 2 3.93 Anisa 115 C GLN 15 3451 3513 2127 -990 145 884 ATÓM 116 ABOUT GLN 15 29.177 31.448 40.213 1,000 2 8.95 Anisa 116 ABOUT GLN 15 3535 4619 2845 -899 519 12 2 5 ATÓM 117 N GLY 16 27.828 29794 40.891 1,000 2 5.86 Anisa 117 N GLY 16 4089 3282 2457 -889 -36 469 ATÓM 118 CA GLY 16 28.812 28.763 40649 1,000 2 9.00 Anisa 118 CA GLY 16 4785 3562 2671 -677 765 255 ATÓM 119 C GLY 16 29.741 28.546 41.814 1,000 5.45 Anisa 119 C GLY 16 3427 3490 2754 -264 1422 673 ATÓM 120 ABOUT GLY 16 30.805 27.955 41.625 1,000 9.63 Anisa 120 ABOUT GLY 16 3925 3267 4068 -66 1997 523 ATÓM 121 N LEU 17 29387 28.979 43015 1,000 2 2.50 Anisa 121 N LEU 17 3266 2713 2569 -39 923 733 ATÓM 122 C A LEU 17 30.234 28727 44.172 1,000 2 1.73 Anisa 122 C A LEU 17 2299 293 1 3025 -282 867 748

SUBSTITUTE SHEET (RULE 26)

WO 99'339 * 4

PCT / G Β98Ό3860

ATÓM 123 CB LEU 1 7 30.124 - 94 - 29.921 45.132 1. 000 2 1.2 3 Anisa 123 CB LEU 17 2137 2858 3071 -62 0 7 1 0 ATÓM 124 CG LEU 17 30.354 31274 44.431 1,000 2 6.1 2 Anisa 124 CG LEU 17 2703 2965 4253 -888 1342 9 3 1 ATÓM 125 CD1 LEU 17 29.962 32.444 45.305 1,000 2 9.8 1 Anisa 125 CD1 LEU 17 2515 2924 5885 -396 463 3 0 3 ATÓM 126 CD2 LEU 17 31.808 31.350 43.974 1,000 3 2.8 4 Anisa 126 CD2 LEU 17 2845 3703 5930 -281 1871 2114 ATÓM 127 C LEU 17 29.886 27.456 44.936 1.000 1 9.3 6 Anisa 127 C LEU 17 2081 2819 2455 -239,545 5 8 0 ATÓM 128 ABOUT LEU 17 28.773 26.920 44.848 1,000 2 1.1 1 Anisa 128 ABOUT LEU 17 2284 3004 2734 -443 107 1 0 5 5 ATÓM 129 N HIS 18 30.838 26.952 45.706 1 · 000 2 1.0 2 Anisa 129 N HIS 18 2124 2752 3109 -314 192 4 9 1 ATÓM 130 CA HIS 18 30.678 25.814 46.615 1.000 1 8.1 1 Anisa 130 CA HIS 18 1569 2996 2315 -460 -28 3 6 1 ATÓM 131 CB HIS 18 29.655 26.149 47.702 1,000 2 1.2 5 Anisa 131 CB HIS 18 1731 3332 3010 -45 280 3 5 4 ATÓM 132 CG HIS 18 29.796 27.515 48.283 1.000 2 3.2 8 Anisa 132 CG HIS 18 2234 3612 2999 211 - 46 - 2 0 ATÓM 133 CD2 HIS 18 28.898 28.535 48.344 1,000 2 4.5 3 Anisa 133 CD2 HIS 18 3112 3479 2728 531 41 4 4 0 ATÓM 134 ND1 HIS 18 30.940 27.977 48.895 1,000 2 6.7 2 Anisa 134 ND1 HIS 18 2938 4039 3173 -151 -569 3 7 ATÓM 135 CE1 HIS 18 30.756 29218 49.307 1.000 2 9.8 0 Anisa 135 CE1 HIS 18 4476 3775 3071 -542 -562 2 7 ATÓM 136 NE2 HIS 18 29.524 29.581 48.985 1.000 30.03 Anisa 136 NE2 HIS 18 4752 3282 3377 216 -148 3 3 7 ATÓM 137 C HIS 18 30266 24.528 45917 1.000 18.57 Anisa 137 C HIS 18 1943 3084 2028 - 951 30 5 9 0 ATÓM 138 ABOUT HIS 18 29.594 23.682 46.532 1,000 1 9.9 2 Anisa 138 ABOUT HIS 18 1949 3125 2493 -777 -87 9 9 ATÓM 139 N GLN 19 30647 24.340 44658 1.000 1 9.2 4 Anisa 139 N GLN 19 2329 2700 2282 -256 298 4 9 4 ATÓM 140 CA GLN 19 30.119 23.206 43.908 1,000 2 1.51 Anisa 140 CA GLN 19 3249 2431 2492 -228 597 3 1 7 ATÓM 141 CB GLN 19 30.446 23.307 42406 1.000 22.89 Anisa 141 CB GLN 19 3231 3058 2408 -148 462 2 4 4 ATÓM 142 CG GLN 19 29.738 24.453 41698 1.000 25.83 Anisa 142 CG GLN 19 3445 3712 2658 -383 -407 5 6 8 ATÓM 143 CD GLN 19 28.223 24.470 41.747 1.000 3 1.5 6 Anisa 143 CD GLN 19 3439 4722 3832 -252 -988 3 5 6 ATÓM 144 OE1 GLN 19 27.521 23.640 41.153 1.000 38.51 Anisa 144 OE1 GLN 19 3869 3649 7115 377 -3045 686 ATÓM 145 NE2 GLN 19 27.621 25.433 42.475 1.000 33.32 Anisa 145 NE2 GLN 19 3303 5695 3663 646 -1109 4 4 9 ATÓM 146 C GLN 19 30.578 21.873 44485 1,000 2 0.3 2 Anisa 146 C GLN 19 2224 2710 2785 -60,514 3 9 4 ATÓM 147 ABOUT GLN 19 29806 20.900 44.473 1.000 19.08 Anisa 147 ABOUT GLN 19 1888 2451 2910 +420 221 257 743 ATÓM 148 N ASP 20 31.800 21.761 44.999 1,000 2 4.0 9 Anisa 148 N ASP 20 3001 3507 2645 -773 -508 4 1 5 ATÓM 149 CA ASP 20 32.268 20.498 45553 1.000 2 1.8 2 Anisa 149 CA ASP 20 1707 3811 2774 -327 -58 3 5 6 ATÓM 150 CB ASP 20 33.780 20.527 45.779 1.000 26.34 Anisa 150 CB ASP 20 1594 4552 3863 -962 236 4 9 0 ATÓM 151 CG ASP 20 34.596 20.517 44.503 1.000 3 4.4 5 Anisa 151 CG ASP 20 2531 5859 4701 -1208 1212 - 2 8 0 ATÓM 152 OD1 ASP 20 34.177 19.982 43.457 1,000 3 3.1 1 Anisa 152 OD1 ASP 20 3768 4 173 4640 -311 1233 -375 ATÓM 153 OD2 ASP 20 35725 2 1.056 44.532 1,000 4 9.7 1

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S / 03S60

Anisa 153 OD2 ASP 20 3 4 4 5 9922 5519 -3116 1711 5 3 ATÓM 154 C ASP 20 31.533 20.179 4C. 862 1.OCO Fl.0 3 Anisa 154 C ASP 20 1S7Ó 2702 34 12 -2 3 1 6 1 6 3 8 8 ATÓM 155 ABOUT ASP 20 31.118 19.038 47.075 1.000 20.80 Anisa 155 ABOUT ASP 20 1162 2583 4157 -72 -139 550 ATÓM 1 5 ó N GLU 21 31.359 21.177 47.729 1. 000 7 7.8 8 Anisa 155 N GLU 2 1 1218 2751 2824 -264 -148 5 1 1 ATÓM 157 C A GLU 2 1 30.599 20.999 48.965 1. . 000 1 6.8 0 Anisa 157 C A GLU 21 1128 2173 3083 -96 46,394 ATÓM 158 CB GLU 21 30.654 22.304 49.781 1,000 2 0.2 3 Anisa 158 CB GLU 21 1366 2620 3731 5 -262 -210 ATÓM 159 CG GLU 21 32.040 22.669 50.307 1 · 000 2 4.6 0 Anisa 159 CG GLU 21 1660 3325 43 5 9 -221 -654 - 3 0 1 ATÓM 160 CD GLU 21 32 .860 23.565 49 402 1,000 2 8.4 6 Anisa 160 CD GLU 21 1191 4348 5275 -498 -1597 1125 ATÓM 161 OE1 GLU 21 33751 24294 49.919 1,000 3 1.1 7 Anisa 161 OE1 GLU 21 2360 4428 5057 -1039 -1094 349 ATÓM 162 OE2 GLU 21 32664 23.590 48.171 1.000 31.16 Anisa 162 OE2 GLU 21 2734 3901 52C3 -1519 -1565 1 2 3 ATÓM 163 C GLU 21 29.159 20.594 48.689 1,000 1 6.4 4 Anisa 163 C GLU 21 1271 2295 2679 -165 -53 4 0 0 ATÓM 164 ABOUT GLU 21 28.599 19.700 49.329 1.000 14.30 Anisa 164 ABOUT GLU 21 1271 2257 1907 -417 -301 3 7 ATÓM 165 N PHE 22 28.548 21.257 47.708 1,000 1 6.1 4 Anisa 165 N PHE 22 1440 2441 2253 -316 -28 3 2 9 ATÓM 166 CA PHE 22 27155 20.947 47327 1.000 1 5.3 6 Anisa 166 CA PHE 22 1530 2012 2294 -262 -173 2 8 1 ATÓM 167 CB PHE 22 26.612 21.967 46.343 1.000 1 5.4 3 Anisa 167 CB PHE 22 1863 2056 1944 -316 -247 1 8 4 ATÓM 168 CG PHE 22 25.119 21.932 46.077 1.00015.59 Anisa 168 CG PHE 22 1822 2141 1962 -299 -170 5 6 1 ATÓM 169 CD1 PHE 22 24.218 21.987 47.129 1,000 1 7.03 Anisa 169 CD1 PHE 22 1923 2605 1943 -410 -162-4 ATÓM 170 CD2 PHE 22 24.606 21.856 44 1,000 1 4.8 4 Anisa 170 CD2 PHE 22 1541 2083 2013 51 -94-15 15 ATÓM 171 CE1 PHE 22 22.861 21938 46.906 1,000 1 5.9 6 Anisa 171 CE1 PHE 22 1844 1805 2414 -159 -64 1 7 7 ATÓM 172 CE2 PHE 22 23243 21.797 44.551 1.00015.81 Anisa 172 CE2 PHE 22 1600 1993 2416 -261 -190-1 7 6 ATÓM 173 CZ PHE 22 22.360 21.853 45.612 1.000 1 4.1 8 Anisa 173 CZ PHE 22 1427 1430 2531 -105 -164 3 2 5 ATÓM 174 C PHE 22 27.049 19.515 46.792 1.000 1 6.2 3 Anisa 174 C PHE 22 1325 2042 2797 -110 165 10 2 ATÓM 175 ABOUT PHE 22 26183 18.751 47.229 1,000 13.2 4 Anisa 175 ABOUT PHE 22 1411 1743 1876 105 -194 3 9 1 ATÓM 176 N ARG 23 27.888 19.097 45.853 1,000 1 5.4 5 Anisa 176 N ARG 23 1585 2313 1971 -167 -80 2 9 9 ATÓM 177 CA ARG 23 27.865 17.746 45.325 1.00015.49 Anisa 177 C A ARG 23 809 2443 2635 50 -41 - 2 ATÓM 178 CB ARG 23 28.928 17.539 44.248 1.000 17.8 1 Anisa 178 CB ARG 23 966 3142 2658 -128 43 - 1 6 6 ATÓM 179 CG ARG 23 28.470 17.928 42.860 1,000 2 5.8 6 Anisa 179 CG ARG 23 2719 4636 2470 -758 -176 - 4 9 ATÓM 180 CD ARG 23 29.485 17.370 41.867 1,000 3 4.6 8 Anisa 180 CD ARG 23 5148 4847 3183 -1533 1634 - 5 4 8 ATÓM 181 NE ARG 23 30.660 18253 41.877 1.000 31.13 Anisa 181 NE ARG 23 2799 4194 4836 305 748 6 6 ATÓM 182 CZ ARG 23 30.703 19.424 41.244 1,000 3 4 .2 4 Anisa 182 CZ ARG 23 2749 4844 5418 (757) 239 7 6 4 ATÓM 183 NH1 ARG 23 29.647 19.856 40.551 1.000 2 8.0 6 Anisa 183 NH1 ARG 23 2714 3685 4263 -721 555 181

SUBSTTTUTE SHEET (RULE 26)

WO 99/33494

PCT / GB98O3860

ATÓM 184 NH2 ARG 2 3 31.830 Anisa 184 NH2 ARG 23 2261 ATÓM 185 C ARU 23 28.045 Anisa 185 C ARG 2 3 1071 ATÓM 186 ABOUT ARG 23 27.335 Anisa 186 ABOUT ARG 23 1443 ATÓM 187 N ARG 24 28.952 Anisa 187 N ARG 24 1024 ATÓM 188 C A ARG 24 29. 193 .ANISOU 188 C A ARG 24 1443 ATÓM 189 CB ARG 24 30.466 Anisa 189 CB ARG 24 1244 ATÓM 190 CG ARG 24 31.787 Anisa 190 CG ARG 24 1438 ATÓM 191 CD ARG 24 32979 Anisa 191 CD ARG 24 1163 ATÓM 192 NE ARG 24 33. 636 Anisa 192 NE ARG 24 5800 ATÓM 193 CZ ARG 24 33. 973 Anisa 193 CZ ARG 24 4738 ATÓM 194 NH1 ARG 24 33.731 Anisa 194 NH1 ARG 24 2650 ATÓM 195 NH2 ARG 24 34.579 Anisa 195 NH2 ARG 24 5339 ATÓM 196 C ARG 24 27.972 Anisa 196 C ARG 24 1549 ATÓM 197 ABOUT ARG 24 27.536 Anisa 197 0 ARG 24 1706 ATÓM 198 N CYS 25 27.355 Anisa 198 N CYS 25 907 1824 ATÓM 199 CA CYS 25 26.105 Anisa 199 ΓΑ CYS 25 942 1838 ATÓM 200 CB CYS 25 25.660 Anisa 200 CB CYS 25 1150 ATÓM 201 SG CYS 2 5 23.973 Anisa 201 SG CYS 25 1465 ATÓM 202 C CYS 25 25.001 Anisa 202 C CYS 25 893 1897 ATÓM 203 0 CYS 25 24.360 Anisa 203 ABOUT CYS 25 1347 ATÓM 204 N LEU 26 24.798 Anisa 204 N LEU 26 1102 ATÓM 205 C A LEU 26 23.766 Anisa 205 CA LEU 26 1190 ATÓM 206 CB LEU 26 23.674 Anisa 206 CB LEU 26 1345 ATÓM 207 CG LEU 26 23.242 Anisa 207 CG LEU 26 1199 ATÓM 208 CD1 LEU 26 23.414 Anisa 208 CD1 LEU 26 1428 ATÓM 209 CD2 LEU 26 21.814 Anisa 209 CD2 LEU 26 1384 ATÓM 210 C LEU 26 23.979 Anisa 210 C LEU 26 1360 ATÓM 211 ABOUT LEU 26 23.011 Anisa 211 0 LEU 26 1660 ATÓM 212 N ARG 27 25.196 Anisa 212 N ARG 27 1518 ATÓM 213 C A ARG 27 25.491 Anisa 213 CA ARG 27 2260 ATÓM 214 CB ARG 27 26.846

-96 - 20.114 41.340 1 .000 J ó. 0 S 532s 6121 -5 62 »-86 16.713 46.420 1 .000 6.15 2061 2589 1'6 7 -32 - 2 3 4 15.687 46.410 1. 000 16:28 2244 2497 -118 - 7 1 - 2 7 7 16.988 47.353 1,000 15:27 2156 2623 -52 -21 2 9 16.003 48.430 1,000 17.70 2589 2693 275 -2,215 16.422 49.148 1,000 2 1.11 3486 3289 484 -257 384 16.217 48.429 1,000 3 0.46 5078 5057 426 441 308 16.537 49.330 1,000 3 3.50 5831 5736 208 370 458 17.804 49.071 1,000 5 1.46 7316 64 3 7, -2,596 -1689 1 1 6 5 18.776 49903 1,000 6.72 6888 6124 -1719 -1821 1 3 1 6 18728 51.213 1,000 4.24 6998 7160 -392 1002 8 4 19.871 49.448 1,000 4 2.82 4428 6503 513 -991 12 16 15.887 49.334 1,000 17:16 2071 2900 129 140 295 14.779 49713 1,000 15:38 1890 2247 72 -388 104 17.011 49.696 1,000 12.91 2176 -254 -386 17.040 50454 1,000 12:45 1949 -178 -480 7 1 18.491 50.697 1,000 11.67 1759 1527 -136 -604 184 18.580 51425 1,000 14.90 1593 2602 -164 -26 - 1 8 16.225 49.769 1,000 11.67 1645 -283 -64 1-86 15.377 50.390 1,000 12.73 1,426 2064 -233 -196 123 16.461 48.470 1,000 11.70 1530 1814 -128 -390 1 15.716 47735 1,000 11:11 1476 1556 -238 -79 -194 16.198 46.285 1,000 11:54 1522 1518 -75 -84 - 2 0 0 17.638 46.019 1,000 12:42 1542 1978 -153 -167 - 40 0 17.993 44539 1,000 14.77 1916 2270 43 131 401 17.885 46.466 1,000 14:45 2061 2047 264 -32 321 14.209 47.780 1,000 12.93 1542 2011 -121 -486 - 1 0 0 13.461 48.008 1,000 13.78 1450 2125 -305 -426 - 5 1 13.721 47.576 1,000 9.14 1729 2108 151 -530 - 1 0 6 12.283 47.574 1,000 15:39 1690 1897 186 141 - 3 6 4

12.122 46. 900 1,000 1 7.0 4

SUBSTTRTTE SHEET (RULE 26)

WO 99.33994

PCT / GB9S '03860

Anisa 214 C3 ARG 2 7 2259 2356 136 1 517 4 9 -248 ATÓM 215 CG ARG 2 7 27.502 1 0. 7 S 0 4ó. 801 1,000 * · 2-5. 0 8 Anisa 215 CC- ARG 27 3110 2837 3583 1105 6 0 ó - 3 9 9 ATÓM 216 CD ARG 27 28.995 10.992 46.457 1,000 3 0.32 Anisa 216 CD ARG 2 7 2976 3836 4710 1190 720 - 1 2 3 1 ATÓM 217 ΝΞ ARG 27 29.818 11.407 47.581 1,000 6.51 Anisa 217 ΝΞ ARG 27 3633 4937 5301 121 391 -1429 ATÓM 218 CZ ARG 27 30.988 12.019 47.560 1,000 3 3.07 Anisa 218 CZ ARG 27 3334 5192 5941 364 661 - 1 6 7 4 ATÓM 219 n - i ARG 27 31565 12.340 46.401 1,000 8.56 Anisa 219 NHL ARG 27 4482 7688 62 8 0 -1305 737 - 1 3 2 6 ATÓM 220 NH2 ARG 27 31.606 12.328 48.701 1,000 4 0.23 Anisa 220 NH2 ARG 27 2891 6127 62 6 6 457 718 - 2 4 6 3 ATÓM 221 C ARG 27 25479 11.630 48.949 1,000 14.66 Anisa 221 C ARG 27 1720 1617 2233 135 -33 - 4 2 ATÓM 222 ABOUT ARG 27 24.968 10.499 49072 1,000 17:44 Anisa 222 ABOUT ARG 27 1981 1533 3114 98 -394 155 ATÓM 223 N ASP 28 26.031 12.308 49.973 1,000 13.72 Anisa 223 N ASP 28 1703 1366 2146 317 -327 319 ATÓM 224 CA ASP 28 26.227 11.701 51.277 1,000 15:33 Anisa 224 C A ASP 28 1886 1704 2234 538 -247 391 ATÓM 225 CB ASP 28 27.541 12.280 51842 1,000 18:31 Anisa 225 CB ASP 28 2092 2709 2155 186 -465 5 4 4 ATÓM 226 CG ASP 28 28.785 11.875 51.083 1,000 2 3.06 Anisa 226 CG ASP 28 2002 3583 317 6 -96 -50 478 ATÓM 227 OD1 ASP 28 28741 10.904 50.290 1,000 2 5.09 Anisa 227 OD1 ASP 28 2515 2855 4163 830 406 440 ATÓM 228 OD2 ASP 28 29.831 12.528 51283 1,000 3 0.05 Anisa 228 OD2 ASP 28 1919 4262 52 3 6 -216 -694 1 0 5 8 ATÓM 229 C ASP 28 25.092 11.910 52.267 1,000 14.90 Anisa 229 C ASP 28 2071 1435 2154 411 -203 217 ATÓM 230 ABOUT ASP 28 24.967 11.093 53.200 1,000 14:50 Anisa 230 ABOUT ASP 28 1878 1501 2132 444 -265 179 ATÓM 231 N LYS 29 24.317 12.975 52.096 1,000 12.90 Anisa 231 N LYS 29 1487 1290 2126 77 -276 ATÓM 232 CA LYS 29 23.265 13.368 53.029 1,000 12.95 Anisa 232 CA LYS 29 1369 1649 1904 -390 1 4 ATÓM 233 CB LYS 29 23.699 14.653 53.763 1,000 12.71 Anisa 233 CB LYS 29 1105 1581 2145 209 -358 - 3 0 ATÓM 234 CG LYS 29 25.016 14.504 54.518 1,000 16:11 Anisa 234 CG LYS 29 1413 1998 2711. 21 -818-16 16 ATÓM 235 CD LYS 29 25.449 15.727 55309 1,000 18:24 Anisa 235 CD LYS 29 2500 1989 2442 -47 - 1140 - 1 4 ATÓM 236 CE LYS 29 26.789 15.445 56302 1,000 19:36 Anisa 236 CE LYS 29 2038 3171 2143 -90 -822-7 2 5 ATÓM 237 NZ LYS 29 27.515 16.696 56.351 1,000 6.61 Anisa 237 NZ LYS 29 2592 3146 4373 -309 -1570 - 3 5 3 ATÓM 238 C LYS 29 21.888 13.550 52.386 1,000 11.62 Anisa 238 C LYS 29 1432 1153 1831 52 -290 2 3 ATÓM 239 ABOUT LYS 29 20.877 13.028 52.880 1,000 12:57 Anisa 239 ABOUT LYS 29 1,426 1556 1792 -97 -282 100 ATÓM 240 N GLY 30 21.779 14.280 51.284 1,000 11.98 Anisa 240 N GLY 30 1359 1454 1741 -5 -310 7 7 ATÓM 241 CA GLY 30 20.510 14.478 50562 1,000 10.93 Anisa 241 CA GLY 30 1192 1497 1465 -158 -116-1 8 ATÓM 242 C GLY 30 19.544 15.433 51.242 1,000 11:15 Anisa 242 C GLY 30 1137 1143 1955 -260 -154-1 ATÓM 243 ABOUT GLY 30 18.337 15.374 50.963 1,000 11:26 Anisa 243 ABOUT GLY 30 1247 1082 1949 -56 -419 104 ATÓM 244 N LEU 3 1 20.064 16. 278 52.129 1,000 10:54 Anisa 244 N LEU 31 1292 895 1821 -98 -367 8 9

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ATÓM 245 C A LEU 3 1 19.272 17.324 52.803 1. 000 7.12 Anisa 245 C A LEU 3 1 1345 1111 1752 46 6 -520FL, 33 ATÓM 246 CB LEU 31 18.465 16.777 53. 975 1,000 14:44 Anisa 246 CB LEU 3 1 1753 1671 2062 -2 84 -80- 1 7 8 ATÓM 247 CG LEU 31 19113 16.629 55333 1,000 17.74 Anisa 247 CG LEU 3 1 2456 2220 2064 -172 -125 499 ATÓM 248 CD1 LEU 31 18.220 15.978 56.371 1,000 6.19 Anisa 248 CD1 LEU 3 1 2716 4691 2543 -1224 -213 10 15 ATÓM 249 CD2 LEU 3 1 20388 15.821 55182 1,000 2.77 Anisa 249 CD2 LEU 31 3121 2633 2899 650 -13 13 8 7 ATÓM 250 C LEU 31 20.176 18.498 53.195 1,000 10.95 Anisa 250 C LEU 31 1041 1129 1989 180 -318-223 ATÓM 251 ABOUT LEU 31 21.376 18.314 53.424 1,000 10.89 Anisa 251 ABOUT LEU 31 1015 1171 1952 69 -160 204 ATÓM 252 N PHE 32 19.570 19.688 53.219 1,000 11:42 Anisa 252 N PHE 32 1134 996 2211 75 -273 6 5 ATÓM 253 CA PHE 32 20.280 20.916 53.545 1,000 10:33 Anisa 253 CA PHE 32 1071 1152 1703 -57 -288 - 3 2 ATÓM 254 CB PHE 32 21.244 21.307 52.422 1,000 12:25 Anisa 254 CB PHE 32 1054 1729 1872 -113 -173 - 5 ATÓM 255 CG PHE 32 20.624 21.346 51.041 1,000 11.94 Anisa 255 CG PHE 32 1158 1572 1809 -281 -148 122 ATÓM 256 CD1 PHE 32 20.522 20.188 50.270 1,000 11:12 Anisa 256 CD1 PHE 32 1070 1308 1846 -182 -458 318 ATÓM 257 CD2 PHE 32 20.145 22.528 50.513 1,000 12:14 Anisa 257 CD2 PHE 32 1618 1353 1639 -300 -185 - 4 6 ATÓM 258 CE1 PHE 32 19.943 20.212 49.015 1,000 12:00 Anisa 258 CE1 PHE 32 1342 1377 1840 -301 -468 332 ATÓM 259 CE2 PHE 32 19.553 22.534 49.266 1,000 12.79 Anisa 259 CE2 PHE 32 1858 1543 1457 -86 -34 2 8 ATÓM 260 CZ PHE 32 19.416 21.376 48.503 1,000 11:50 Anisa 260 CZ PHE 32 1623 1414 1331 -76 -272 217 ATÓM 261 C PHE 32 19.310 22.071 53.762 1,000 9.82 Anisa 261 C PHE 32 1015 1042 1674 -120 -367-7 7 ATÓM 262 0 PHE 32 18.165 21.990 53.285 1,000 11:29 Anisa 262 ABOUT PHE 32 1097 1286 1906 -95 -495-7 7 ATÓM 263 N TYR 33 19.736 23.099 54.493 1,000 12.68 Anisa 263 N TYR 33 1606 1053 2158 -57 -766- 1 5 9 ATÓM 264 CA TYR 33 18.945 24.335 54.607 1,000 10.64 Anisa 264 CA TYR 33 1491 1173 1380 -77 -97-13 13 ATÓM 265 CB TYR 33 19.141 25.022 55.955 1,000 10.85 Anisa 265 CB TYR 33 1019 1725 1379 -260 -224-1 6 4 ATÓM 266 CG TYR 33 18.545 24.331 57.156 1,000 10.71 Anisa 266 CG TYR 33 1173 1552 1342 -45 -230-1 1 7 ATÓM 267 CD1 TYR 33 17.266 24.643 57619 1,000 11.64 Anisa 267 CD1 TYR 33 1385 1441 1596 -68 83-94 ATÓM 268 CE1 TYR 33 16.694 24.023 58.719 1,000 13.60 Anisa 268 CE1 TYR 33 1879 1483 1804 -147 339-2 2 6 ATÓM 269 CD2 TYR 33 19.273 23.364 57.853 1,000 4.14 Anisa 269 CD2 TYR 33 1604 2040 1689 132 -509 127 ATÓM 270 CE2 TYR 33 18.711 22.752 58.964 1,000 15.75 Anisa 270 CE2 TYR 33 1872 2227 1886 -187 -701 433 ATÓM 271 CZ TYR 33 17.438 23.078 59.387 1,000 16.2 Anisa 271 CZ TYR 33 2205 1939 1942 -332 -154 300 ATÓM 272 OH TYR 33 16.919 22.454 60504 1,000 19.95 Anisa 272 OH TYR 33 3412 2154 2015 -60 278 400 ATÓM 273 C TYR 33 19.357 25.253 53.452 1,000 10.92 Anisa 273 C TYR 33 1249 1448 1453 -125 -271 149 ATÓM 274 ABOUT TYR 33 20.514 25.192 53.006 1,000 11:50 Anisa 274 ABOUT TYR 33 1204 1375 1791 -98 -270 281 ATÓM 275 N LEU 34 18.399 26.049 53.000 1,000 11:28

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S '03860

Anisa 275 N LEU 3 4 1159 12 6 5 1862 -210 -149 1 2 1 ATÓM 2 7 6 C A LEU 34 18.577 26.942 51.864 1. JL2-000 ,. 9 9 Anisa 2 7 6 C A LEU 3 4 1565 144 4 1926 81 -478 274 ATÓM 277 CB LEU 34 17.757 26.420 50682 i. 000 13.96 Anisa 277 CB LEU 34 2007 1301 1995 -430 -458 3 2 1 ATÓM 278 CG LEU 34 17.990 27.112 49.334 1,000 13.81 Anisa 278 CG LEU 34 2085 1322 1839 -331 -365 198 ATÓM 279 CD1 LEU 34 19 .308 26.691 4 3.704 1,000 15.94 Anisa 279 CD1 LEU 3 4 2123 1793 2 140 -10 -313 607 ATÓM 280 CD2 LEU 34 16.818 26.799 43.411 1,000 16:36 Anisa 280 CD2 LEU 34 2186 1837 2193 122 -721 134 ATÓM 281 C LEU 34 18.195 28.361 52.241 1,000 3.13 Anisa 281 C LEU 34 1676 1418 1857 -643 2 1 R ATÓM 282 ABOUT LEU 34 17.055 28.647 52.595 1,000 13.99 Anisa 282 ABOUT LEU 34 1690 1281 2 3 44 140 -715 8 5 ATÓM 283 N THR 35 19.148 29.283 52 .175 1,000 3.15 Anisa 283 N THR 35 1837 1584 22 88 -118 -625 - 3 ATÓM 284 CA THR 35 18.918 30.704 52.369 1,000 14.80 Anisa 284 CA THR 35 1866 1560 2196 -169 -175-14 14 ATÓM 285 CB THR 35 20.013 31.366 53.232 1,000 15.65 Anisa 285 CB THR 35 2025 1719 2202 -149 -204-2 8 1 ATÓM 286 OG1 THR 35 21.276 31.115 52.601 1,000 18.81 Anisa 286 OG1 THR 35 1885 2679 2583 -279 -229-7 2 8 ATÓM 287 CG2 THR 35 20.138 30.811 54.622 1,000 18.84 Anisa 287 CG2 THR 35 2523 2207 2427 -850 -510 155 ATÓM 288 C THR 35 18.915 31456 51.043 1,000 7.15 Anisa 288 C THR 35 1904 1473 2348 -57 -283-7 0 ATÓM 289 ABOUT THR 35 19.209 30909 49.973 1,000 15:00 Anisa 289 ABOUT THR 35 2034 1520 2145 -215 -372 8 9 ATÓM 290 N ASP 36 18.564 32.739 51086 1,000 17:46 Anisa 290 N ASP 36 2302 1366 2968 -209 -767 - 1 2 0 ATÓM 291 CA ASP 36 18.618 33.606 49924 1,000 17.91 Anisa 291 CA ASP 36 2150 1592 30 (53 112 -660 8 6 ATÓM 292 CB ASP 36 20.063 33845 49 .471 1,000 17.91 Anisa 292 CB ASP 36 2153 1584 3 067 84 -587 - 4 2 ATÓM 293 CG ASP 36 20948 34.545 50469 1,000 19:23 Anisa 293 CG ASP 36 2575 2160 2571 -642 -324 181 ATÓM 294 OD1 ASP 36 20.426 35.304 51325 1,000 4.17 Anisa 294 OD1 ASP 36 2843 3055 3284 152 -1013 - 6 5 2 ATÓM 295 OD2 ASP 36 22.199 34.355 50.412 1,000 2 1.00 Anisa 295 OD2 ASP 36 2637 2571 2772 -382 - 834 - 3 9 3 ATÓM 296 C ASP 36 17.783 33.038 48784 1,000 18:20 Anisa 296 C ASP 36 2402 1736 2779 -446 -390 191 ATÓM 297 ABOUT ASP 36 18.222 33063 47.629 1,000 18.98 Anisa 297 0 ASP 36 2127 2022 3062 -464 - 60 - 2 5 2 ATÓM 298 N CYS 37 16.593 32.547 49.077 1,000 17:22 Anisa 298 N CYS 37 1873 2190 2479 63 -350-1 ATÓM 299 CA CYS 37 15.730 31.945 48.043 1,000 15.98 Anisa 299 CA CYS 37 1997 1590 2485 -81 -65 - 18 4 ATÓM 300 CB CYS 37 15.621 30.423 48252 1,000 18.87 Anisa 300 CB CYS 37 2112 1790 3268 -114 -405 570 ATÓM 301 SG CYS 37 14.753 29.917 49.759 1,000 19:42 Anisa 301 SG CYS 37 2532 1683 3164 -74 -230 322 ATÓM 302 C CYS 37 14.349 32.580 47.958 1,000 16:12 Anisa 302 C CYS 37 1992 1669 2465 -175 -503 1 6 ATÓM 303 ABOUT CYS 37 13.483 32.032 47.253 1,000 2 0.60 Anisa 303 ABOUT CYS 37 2761 1769 3296 -241 -1333 5 1 ATÓM 304 N GLY 38 14.125 33714 48.617 1,000 17.89 Anisa 304 N GLY 38 1847 1572 3381 209 -898-1 1 1 1 ATÓM 305 CA GLY 38 12.850 34.404 48587 1,000 18:16 Anisa 305 CA GLY 38 1608 2126 3164 14 1 -999-6

SUBSTITUTE SHEET (RULE 26)

WO 99/33494

PCT / GB98.O3860

- 100 -

ATÓM 3 06 C G L. ' 3 S 11.543 33.864 49.589 1 00021.98 Anisa 3 0 6 C GLY 33 2598 2574 3180 262 -4 5 5 ATÓM 307 ABOUT GLY 38 10.677 34273 49.499 1. 000 2.75 Anisa 307 0 GLY 38 2542 3027 3073 24 1 79-97 ATÓM 308 N LEU 39 12.241 32.982 50.501 1. 000 2 1.93 Anisa 30S N LEU 39 2112 3318 2903 - 6 5 -102 -15 4 ATÓM 309 C A LEU 39 11.443 32.357 51545 1,000 6.16 Anisa 309 C A LEU 39 3141 3610 3188 -1071 162 - 4 0 1 ATÓM 310 CB LEU 39 11.220 30.868 51.277 1,000 8.13 Anisa 310 C3 LEU 39 2980 3192 4516 -352 -848 258 ATÓM 311 CG LEU 39 10.296 30.434 50.157 1,000 7.39 Anisa 311 CG LEU 39 3352 2591 4463 541 -637 -1052 ATÓM 312 CD1 LEU 39 10.472 28.940 49. 910 1,000 8.66 Anisa 312 CD1 LEU 39 3375 2293 5221 581 -150-19 0 ATÓM 313 CD2 LEU 39 8838 30.768 50.478 1,000 3 0.62 Anisa 313 CD2 LEU 39 3155 2985 5496 1275 -1485 - 2 0 7 ATÓM 314 C LEU 39 12.060 32.430 52.949 1,000 6.26 Anisa 314 C LEU 39 2868 3969 3143 -796 170 335 ATÓM 315 0 LEU 39 13.105 31.861 53 .266 1,000 5.57 Anisa 315 0 LEU 39 4990 4057 4470 804 -630 320 ATÓM 316 N THR 40 11.388 33136 53827 1,000 6.61 Anisa 316 N THR 40 3425 3883 2803 -703 -191 102 ATÓM 317 CA THR 40 11.676 33.329 55228 1,000 22.95 Anisa 317 CA THR 40 1972 3864 2886 4 -608,518 ATÓM 318 C THR 40 10.380 33.424 56031 1,000 27.03 Anisa 318 C THR 40 2331 4900 3040 -690 -220 - 3 ATÓM 319 0 THR 40 9254 33.316 55537 1,000 25.98 Anisa 319 0 THR 40 2148 4860 2864 -546 36-7 2 0 ATÓM 320 CB THR 40 12.476 34.624 55.456 1,000 7.16 Anisa 320 CB THR 40 2646 4799 2874 -932 -391 148 ATÓM 321 OG1 THR 40 11.639 35.687 54.986 1,000 6.24 Anisa 321 OG1 THR 40 5158 3872 4740 -472 -136 660 ATÓM 322 CG2 THR 40 13.771 34.669 54.659 1,000 4.29 Anisa 322 CG2 THR 40 5268 3289 4470 -1303 2206 429 ATÓM 323 N ASP 41 10.524 33.635 57.346 1,000 8.20 Anisa 323 N ASP 41 2270 5223 3223 -711 -317 - 4 7 8 ATÓM 324 CA ASP 41 9324 33.604 58.191 1,000 25.10 Anisa 324 CA ASP 41 1935 4633 2968 13 -552 - 5 0 5 ATÓM 325 C ASP 41 8.418 34.785 57896 1,000 2 4.69 Anisa 325 C ASP 41 2686 3839 2855 -446 - 750 - 2 4 1 ATÓM 326 0 ASP 41 7219 34.846 58.163 1,000 4.79 Anisa 326 0 ASP 41 2757 2721 3941 174 - 584 - 1 4 1 ATÓM 327 CB ASP 41 9728 33.549 59.678 1,000 8.21 Anisa 327 CB ASP 41 2221 5503 2995 892 -594 - 5 5 ATÓM 328 CG ASP 41 9.892 32.129 60.180 1,000 4 2.46 Anisa 328 CG ASP 41 6437 5911 3784 -1196 -1257 826 ATÓM 329 OD1 ASP 41 9.705 31.161 59401 1,000 5 5.96 Anisa 329 OD1 ASP 41 12184 5138 3940 -2,654 -81 1 2 4 9 ATÓM 330 OD2 ASP 41 10.214 31.951 61383 1,000 6 1.55 Anisa 330 OD2 ASP 41 10370 7470 5548 -4,396 -4719 2 3 0 9 ATÓM 331 N THR 42 8991 35807 57305 1,000 2 9.30 Anisa 331 N THR 42 3761 4531 2839 -1404 -1089-7 2 ATÓM 332 C A THR 42 8.255 36976 56863 1,000 3 3.69 Anisa 332 C A THR 42 4852 3472 4475 -1524 -819 '- 1 2 ATÓM 333 C THR 42 7.199 36.598 55.834 1,000 9.14 Anisa 333 C THR 42 3354 3051 4667 204 -648-2 7 7 ATÓM 334 0 THR 42 6,026 36.969 55.844 1,000 6.90 Anisa 334 0 THR 42 3578 2980 7462 603 -176 643 ATÓM 335 CB THR 42 9,282 37.967 56281 1,000 4 0.80 Anisa 335 CB THR 42 5831 4318 5354 -2254 -450 3 7 ATÓM 336 OG1 THR 42 10.288 38.317 57.263 1. 000 4.30

SUSSTTTUTE SHEET (RULE 26) \\ / 90/33994

PCT / GB9S / 03860

- 101 -

ANISOU 33b OG1 THR 4 2 6998 3Ó82 G 9 12 - 3 1 6 4 -143 1 7 ATÓM 337 CG2 THR 4 2 8.582 39.253 55.872 1000-13 ». 5 9 Anisa 337 CG2 THR 4 2 9083 3877 4 3 63 -2,166 -104S 2 3 S ATÓM 338 N GLU 4 3 7 .573 35. 773 54.862 1,000 3 1.74 Anisa 338 N GLU 43 3380 4360 4319 -673 -223 - 7 N 2 ATÓM 339 C A GLU 4 3 6647 35.355 53.810 1,000 3 5.40 Anisa 339 C A GLU 43 485Ó 4683 3913 -1510 -6ó0 329 ATÓM 340 C GLU 43 5643 34324 54.330 1,000 2 8.03 Anisa 340 C GLU 43 2988 3297 4363 -41 -919 168 ATÓM 341 0 GLU 43 4.560 34 .138 53 .764 1,000 8.18 Anisa 341 0 GLU 43 3818 2970 7 717 - 6 6 -2773 1 4 6 9 ATÓM 342 CB GLU 43 7.423 34.811 52.608 1,000 3 8.89 Anisa 342 CB GLU 43 4464 6532 3779 -2,546 -860-3 3 9 3 ATÓM 343 CC- GLU 43 8.462 35745 52.010 1,000 5.47 Anisa 343 CG GLU 4 3 5175 7105 5377 -2,936 -92-2 8 9 ATÓM 344 CD GLU 43 9,750 35764 52826 1,000 4 6.40 Anisa 344 CD GLU 43 4506 7977 51 45 -3,155 547 - 1 2 1 0 ATÓM 345 OE1 GLU 43 9775 36.447 53.880 1,000 5.20 Anisa 345 OE1 GLU 43 8741 7607 2-7 -2062 -1002 - 6 6 9 ATÓM 346 OE2 GLU 43 10.706 35.080 52.433 1,000 6.77 Anisa 346 OE2 GLU 43 4592 8930 8050 -2,652 938 - 1 2 5 8 ATÓM 347 N LEU 44 5.980 33.645 55426 1,000 2 2.72 Anisa 347 N LEU 44 2508 2161 3964 464 -476 - 4 5 0 ATÓM 348 C A LEU 44 5.117 32.592 55.959 1,000 6.76 Anisa 348 C A LEU 44 4009 1973 4187 140 570-9 8 6 ATÓM 349 CB LEU 44 5.978 31.585 56.727 1,000 8.25 Anisa 349 CB LEU 44 5094 2194 3448 -153 277-5 5 6 2 ATÓM 350 CG LEU 44 5284 30494 57.533 1,000 3 2.03 Anisa 350 CG LEU 44 5971 2801 33 98 -279 1192 - 6 7 ATÓM 351 CD1 LEU 44 4.485 29.535 56.656 1,000 7.95 Anisa 351 CD1 LEU 44 7665 2239 4514 -1148 2039 - 1 4 0 4 ATÓM 352 CD2 LEU 44 6,302 29.703 58 .361 1,000 3 6.97 Anisa 352 CD2 LEU 44 7096 2869 4080 1150 2171 186 ATÓM 353 C LEU 44 4,000 33.145 56.841 1,000 1.10 Anisa 353 C LEU 44 3835 3182 4800 -700 836 - 2 2 0 5 ATÓM 354 0 LEU 44 2,913 32.543 56.867 1,000 3 0.19 Anisa 354 0 LEU 44 4402 3299 3768 -1248 870 - 2 ATÓM 355 N ALA 45 4238 34.247 57.547 1,000 8.74 Anisa 355 N ALA 45 2897 2938 5083 -562 710 - 2 0 6 0 ATÓM 356 CA ALA 45 3382 34.751 58.623 1,000 2 7.09 Anisa 356 CA ALA 45 2716 2817 4761 -751 466 - 2 1 4 0 ATÓM 357 C ALA 45 1.943 35014 58.195 1,000 2 4.95 Anisa 357 C ALA 45 2697 3110 3673 -784 709 - 1 2 56 ATÓM 358 0 ALA 45 1,021 34.515 58.875 1,000 2 2.50 Anisa 358 0 ALA 45 2762 2585 3201 -565 560 - 1 2 3 4 ATÓM 359 CB ALA 45 3.975 36.005 59.248 1,000 3 6.30 Anisa 359 CB ALA 45 3259 4219 6315 -1912 1332 - 3 04 ATÓM 360 N SER 46 1729 35.779 57,128 1,000 6.85 Anisa 360 N SER 46 3258 3756 3187 -1732 619 - 1 1 8 5 ATÓM 361 C A SER 46 0.380 36.052 56,542 1,000 2 4.97 Anisa 361 CA SER 46 3686 3189 261L -1223 511 - 1 1 0 6 ATÓM 362 CB SER 46 0422 36.950 55392 1,000 3 2.35 Anisa 362 CB SER 46 5428 3467 3 3 95 -2232 71 - 4 5 8 ATÓM 363 OG SER 46 0.630 38289 55772 1,000 4 5.77 Anisa 363 OG SER 46 7730 3349 6313 -2,746 2499 - 8 0 6 ATÓM 364 C SER 46 -0,408 34.787 56.307 1,000 2 0.63 Anisa 364 C SER 46 2797 2469 2 5 72 -423 -151-5 5 4 2 ATÓM 365 0 SER 46 -1. 578 34. 672 56.698 1,000 i 1.93 Anisa 365 0 SER 46 3120 2486 2 7 2 5 -559 305-4 4 0 3 ATÓM 366 N ALA 47 0211 3 3 .855 55. 5.90 1. OOO 122.39 Anisa 366 you ALA 4 7 3096 2167 32 4 < -488 394 - 3 7 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 102 -

ATÓM 367 C A ALA 47 -0,397 32.596 55.176 1,000 1-9.5 4 Anisa 367 C A ALA 4 7 2746 1863 2814 -289 3o2 - 6 ATÓM 368 CB ALA 47 0548 31. 900 54191 1,000 3.54 Anisa 368 CB ALA 4 7 3524 1717 3705 -617 1236 - 1 5 9 ATÓM 369 C ALA 47 -0,715 31.714 56.381 1,000 19.95 Anisa 369 C ALA 47 2282 2546 2752 -327 19 2 5 6 ATÓM 370 ABOUT ALA 4 7 -1,836 31199 56.518 1,000 19.66 Anisa 370 ABOUT ALA 47 2489 2589 2393 -614 211 - 16 5 ATÓM 371 N LYS 48 0.270 31558 57268 1,000 18:24 Anisa 371 N LYS 48 2713 1966 2253 -210 -139-9 1 2 ATÓM 372 C A LYS 48 0042 30.782 58.486 1,000 19:33 Anisa 372 C A LYS 48 2398 2625 2321 43 -312 -563 ATÓM 373 C LYS 48 -1,110 31.329 59.322 1,000 2 0.57 Anisa 373 C LYS 48 2476 2556 2785 -326 83 - 5 6 7 ATÓM 374 ABOUT LYS 48 -2,022 30.613 59.771 1,000 2 0.34 Anisa 374 ABOUT LYS 48 3207 2598 1923 -521 139 - 3 3 0 ATÓM 375 CB LYS 48 1352 30.758 59294 1,000 4.61 Anisa 375 CB LYS 48 2400 3792 3158 -258 -556 - 8 0 ATÓM 376 CG LYS 48 1,237 29.873 60531 1,000 3 0.84 Anisa 376 CG LYS 48 4306 4044 3366 -291 -1504 277 ATÓM 377 CD LYS 48 1.837 30.575 61736 1,000 4 1.45 Anisa 377 CD LYS 48 6742 5755 3251 -1067 -1382 - 3 6 6 ATÓM 378 CE LYS 48 1.625 29.717 62966 1,000 4 1.63 Anisa 378 CE LYS 48 6620 6124 3073 -466 -1047 - 3 ATÓM 379 NZ LYS 48 1.074 30.497 64112 1,000 42.62 Anisa 379 NZ LYS 48 5883 6866 3444 460 -1194 - 4 2 5 ATÓM 380 N ASP 49 -1,110 32.625 59607 1,000 19:18 Anisa 380 N ASP 49 2348 2602 2337 -464 100-8 0 6 ATÓM 381 CA ASP 49 -2,127 33.243 60433 1,000 2 1.95 Anisa 381 CA ASP 49 2555 2986 2801 -791 617 -1035 ATÓM 382 CB ASP 49 -1,868 34756 60611 1,000 23.97 Anisa 382 CB ASP 49 2827 2872 3409 -250 -79 - 1 32 ATÓM 383 CG ASP 49 -0,681 35.078 61492 1,000 5.41 Anisa 383 CG ASP 49 2787 3405 3464 -365 113 -1866 ATÓM 384 OD1 ASP 49 -0,153 34.153 62143 1,000 3 0.75 Anisa 384 OD1 ASP 49 3572 4181 3932 -254 -967 - 1,667 ATÓM 385 OD2 ASP 49 -0,235 36.256 61563 1,000 3 0.78 Anisa 385 OD2 ASP 49 3303 3649 4742 -710 342 -2 4 13 ATÓM 386 C ASP 49 -3,543 33.061 59.904 1,000 2 1.44 Anisa 386 C ASP 49 2465 2651 3030 -388 540-9 0 0 ATÓM 387 ABOUT ASP 49 -4,476 32.770 60654 1,000 2 0.72 Anisa 387 ABOUT ASP 49 2346 2181 3347 -279 550 - 7 2 7 ATÓM 388 N LEU 50 -3,731 33.269 58596 1,000 3.28 Anisa 388 N LEU 50 2942 2712 3191 -1251 216 - 6 3 4 ATÓM 389 CA LEU 50 -5,086 33.185 58.068 1,000 2 2.94 Anisa 389 CA LEU 50 3104 1796 3815 -575 -205 - 1,079 ATÓM 390 CB LEU 50 -5,204 33861 56696 1,000 8.78 Anisa 390 CB LEU 50 3948 2453 4535 -852 - 755 - 2 5 4 ATÓM 391 CG LEU 50 -6,620 34246 56.260 1,000 2 5.30 Anisa 391 CG LEU 50 3800 2294 3520 29 325 - 5 3 1 ATÓM 392 CD1 LEU 50 -7,552 34.478 57.441 1,000 4 4.77 Anisa 392 CD1 LEU 50 6382 4432 6196 -475 3026 - 1 0 5 0 ATÓM 393 CD2 LEU 50 -6,625 35.485 55385 1,000 3 2.52 Anisa 393 CD2 LEU 50 5861 1962 4533 752 353 - 4 3 3 ATÓM 394 C LEU 50 -5,566 31.737 57.982 1,000 2 1.12 Anisa 394 C LEU 50 2559 1870 3595 -643 741 - 1 2 7 0 ATÓM 395 ABOUT LEU 50 -6,772 31.494 58175 1,000 2 1.13 Anisa 395 ABOUT LEU 50 2491 2457 3083 -543 579 - 1 0 9 6 ATÓM 396 N VAL 51 -4,681 30.769 57.715 1,000 16:27 Anisa 396 N VAL 51 2517 1843 1823 -302 -3 6 6 6 ATÓM 397 C A VAL 51 -5,186 29.370 57.701 1,000 7.18

SUBSTTriTTE SHEET (RULE 26)

WO 99/33994

PCT / G B98 / 03860

- 103 -

ANISOU 397 C A VAL 5 1 315 4 1763 1947 -401 -15 - 42 ATÓM 393 CB VAL 51 -4. 2S1 28.415 56.889 1,000 r-e-O 7 Anisa 398 CB VAL 51 2981 1629 14 9 6 -621 -255 - 5 0 0 ATÓM 399 CG1 VAL 51 -3,002 28.114 57 .663 I '. 000 1 S. 9 9 Anisa 399 CG1 VAL 51 2959 2382 18''5 -383 -100 302 ATÓM 400 CG2 VAL 51 -5 .006 27.119 56.497 1,000 2.16 Anisa 400 CG2 VAL 51 4569 2121 172 8 -1393 64-8 6 9 ATÓM 401 C VAL 51 -5,446 28899 59114 1,000 17.74 Anisa 401 C VAL 51 2508 2223 2009 -435 141 - 4 4 5 ATÓM 402 ABOUT VAL 51 -6,430 28187 59.346 1,000 19.76 Anisa 402 ABOUT VAL 51 3005 2160 2345 -692 726 - 1 0 2 0 ATÓM 403 N ILE 52 -4,671 29.263 60.125 1,000 2 0.23 Anisa 403 N ILE 52 2980 2945 1760 -649 364-9 0 2 ATÓM 404 CA ILE 52 -4,990 28.875 61507 1,000 2 0.17 Anisa 404 CA ILE 52 3200 2665 1800 -758 62-1 13 4 ATÓM 405 CB ILE 52 -3,847 29.230 62469 1,000 2 1.31 Anisa 405 CB ILE 52 3294 3151 1652 -449 463 - 1 0 4 3 ATÓM 406 CG2 ILE 52 -4,238 29.178 63931 1,000 1.29 Anisa 406 CG2 ILE 52 3543 2826 1719 -362 528 - 6 8 9 ATÓM 407 CG1 ILE 52 -2,619 28.346 62217 1,000 5.37 Anisa 407 CG1 ILE 52 3213 3819 2603 -307 727 - 1 0 8 0 ATÓM 408 CD1 ILE 52 -2,871 26.872 62470 1,000 8.56 Anisa 408 CD1 ILE 52 3474 3578 3793 106 178 - 1 1 1 1 ATÓM 409 C ILE 52 -6,284 29.514 61.950 1,000 2.44 Anisa 409 C ILE 52 3119 3216 2190 -710 644 - 1 2 2 8 ATÓM 410 0 ILE 52 -7,072 28.856 62647 1,000 3.23 Anisa 410 0 ILE 52 3390 3654 178LE -766 758 -1246 ATÓM 411 N ASP 53 -6,519 30.754 61530 1,000 2 3.33 Anisa 411 N ASP 53 2897 3064 2 9 03 -626 700 -1361 ATÓM 412 CA ASP 53 -7,826 31335 61897 1,000 4.49 Anisa 412 CA ASP 53 2818 3347 3141 -759 781 - 1 4 5 ATÓM 413 CB ASP 53 -7,942 32.781 61411 1,000 7.43 Anisa 413 CB ASP 53 2854 3335 4235 -434 819 -1446 ATÓM 414 CG ASP 53 -9,309 33.397 61.570 1,000 3 0.99 Anisa 414 CG ASP 53 3166 4281 4326 36 1241 - 1 2 1 4 ATÓM 415 OD1 ASP 53 -9,657 33.779 62705 1,000 7.26 Anisa 415 OD1 ASP 53 4369 4569 5220 153 1263 - 2 7 2 3 ATÓM 416 OD2 ASP 53 -10,050 33.491 60553 1,000 8.45 Anisa 416 OD2 ASP 53 3393 6043 5173 810 558 - 1 6 4 7 ATÓM 417 C ASP 53 -8,953 30.495 61316 1,000 2 4.64 Anisa 417 C ASP 53 3028 3701 2634 -919 372 - 1 02 1 ATÓM 418 ABOUT ASP 53 -10,011 30327 61915 1,000 8.52 Anisa 418 ABOUT ASP 53 3399 3835 3603 -1,519 961 - 2 1 5 1 ATÓM 419 N PHE 54 -8,744 29.978 60108 1,000 2 2.04 Anisa 419 N PHE 54 2921 2974 2479 -573 174-7 0 4 ATÓM 420 CA PHE 54 -9,772 29.187 59432 1,000 19.99 Anisa 420 CA PHE 54 2253 2879 2463 -421 771-9 7 8 ATÓM 421 CB PHE 54 -9,423 29.030 57.942 1,000 18:45 Anisa 421 CB PHE 54 2856 1983 2171 -65 426 - 5 1 7 ATÓM 422 CG PHE 54 -10,493 28.292 57.145 1,000 2 1.36 Anisa 422 CG PHE 54 3063 2735 2318 -646 599 - 6 7 ATÓM 423 CD1 PHE 54 -11,714 28.906 56.933 1,000 3.18 Anisa 423 CD1 PHE 54 3199 2783 2826 -703 -29- 6 2 4 ATÓM 424 CD2 PHE 54 -10,293 27035 56.6 L9 1,000 2 3.32 Anisa 424 CD2 PHE 54 3482 2802 2577 -689 212-8 5 8 ATÓM 425 CE1 PHE 54 -12,719 28291 56.241 1,000 126.45 Anisa 425 CE1 PHE 54 3345 3696 3008 -1418 1129 - 5 6 4 ATÓM 426 CE2 PHE 54 -11,303 26.375 55.921 1. OOC 125.65 AIJISOU 426 CE2 PHE 54 3750 3815 2182 -1404 1,607 - 1 0 0 ' ATÓM 427 CZ PHE 54 -12,522 27.013 55.725 1. 000 2 6.1 7 Anisa 427 CZ PHE 54 343 3 3 830 2679 -1829298 -813

SUBSTITUTE SHEET (RULE 26)

WO 99/33094

PCT / GBOS'03860

- 104 -

ATÓM 42S C Ľ rr 54 -9 .959 27.654 60132 1. 000 19:44 Anisa 428 C PHE 54 2340 3 430 1617 -834 3-i, -7 5 a ATÓM 429 ABOUT PHE 54 -11. 087 27.450 60386 1. 000 2 2.11 Anisa 429 ABOUT PHE 54 2601 3066 2734 -'9 4 8 1016 -14 6 6 ATÓM 430 N PHE 55 -8 .882 27.166 60448 1,000 2 0.59 Anisa 430 N PHE 55 2728 3375 1720 -666 180-6 6 1 1 ATÓM 431 CA PHE 5 5 -8,966 25.927 61212 1,000 2.59 Anisa 431 CA PHE 55 3092 3671 1820 -728 383 - 3 7 2 ATÓM 432 CB PHE 55 -7,579 25.360 61478 1,000 2 1.93 Anisa 432 CB PHE 55 3163 3622 1549 -692 287 - 1 6 8 ATÓM 433 CG PHE 55 -6,790 24.833 60284 1,000 2 0.60 Anisa 433 CG PHE 55 3034 2998 1793 -1004 365 - 3 6 5 ATÓM 434 CD1 PHE 55 -7,352 24.526 59.057 1,000 18.72 Anisa 434 CD1 PHE 55 2300 3095 1717 -1,078 587 - 2 7 1 ATÓM 435 CD2 PHE 55 -5,430 24.615 60.385 1,000 6.18 Anisa 435 CD2 PHE 55 3132 2490 1241 -926 128 - 4 9 6 ATÓM 436 CE1 PHE 55 -6,609 24.037 58.014 1,000 18.92 Anisa 436 CE1 PHE 55 2455 2761 1971 -844 435 - 5 4 2 ATÓM 437 CE2 PHE 55 -4,672 24.124 59352 1,000 18:58 Anisa 437 CE2 PHE 55 3291 2606 1163 -478 63-2 9 9 ATÓM 438 CZ PHE 55 -5,256 23.814 58134 1,000 17.68 Anisa 438 CZ PHE 55 2660 2567 1490 -380 129-8 0 6 ATÓM 439 C PHE 55 -9,684 26.111 62546 1,000 2 4.99 Anisa 439 C PHE 55 3310 4138 2046 -830 646 - 4 1 5 ATÓM 440 ABOUT PHE 55 -10,532 25.281 62872 1,000 3 0.29 Anisa 440 ABOUT PHE 55 3802 4943 2763 -1527 1314 - 1 0 0 0 ATÓM 441 N GLU 56 -9,330 27.144 63.311 1,000 23.65 Anisa 441 N GLU 56 2864 4109 2013 -634 936 - 5 2 5 ATÓM 442 CA GLU 56 -9,868 27.355 64636 1,000 3 0.01 Anisa 442 CA GLU 56 3632 5378 2394 -1050 1465-9 9 4 ATÓM 443 CB GLU 56 -8,998 28.333 65436 1,000 3 6.40 Anisa 443 CB GLU 56 4531 6933 2367 -1606 1318-162 3 ATÓM 444 CG GLU 56 -7,666 27.827 65916 1,000 4 1.89 Anisa 444 CG GLU 56 5006 8196 2713 -1457 404-190 0 ATÓM 445 CD GLU 56 -6,787 28.880 66575 1,000 8.94 Anisa 445 CD GLU 56 6081 9310 3202 -2278 -73 - 2 05 2 ATÓM 446 OE1 GLU 56 -5,694 28.515 67078 1,000 60.73 Anisa 446 OE1 GLU 56 8034 12274 2769 -3,208 -2335 266 ATÓM 447 OE2 GLU 56 -7,145 30.084 66614 1,000 8.51 Anisa 447 OE2 GLU 56 8742 9338 4151 -2,088 1096 - 3 8 5 1 ATÓM 448 C GLU 56 -11,289 27.920 64617 1,000 3 0.60 Anisa 448 C GLU 56 3764 4923 2941 -977 1967 - ATÓM 449 ABOUT GLU 56 -12,058 27.542 65504 1,000 5.21 Anisa 449 ABOUT GLU 56 4384 5304 3690 -1136 2653 - 1 2 3 5 ATÓM 450 N HIS 57 -11,603 28.805 63673 1,000 3 0.00 Anisa 450 N HIS 57 3730 4846 2823 -654 1684 - 1 5 7 2 ATÓM 451 CA HIS 57 -12,854 29.559 63759 1,000 3 3.51 Anisa 451 CA HIS 57 3853 5101 3778 -519 1673 - 1 9 1 0 ATÓM 452 CB HIS 57 -12,536 31.046 63991 1,000 3 3.40 Anisa 452 CB HIS 57 3844 5183 3664 -411 1545 - 2 2 5 0 ATÓM 453 CG HIS 57 -11,577 31.344 65095 1,000 5.13 Anisa 453 CG HIS 57 4497 5409 3444 -505 1340-1 9 9 2 ATÓM 454 CD2 HIS 57 -10,361 31.946 65071 1,000 5.26 Anisa 454 CD2 HIS 57 4837 5214 3345 -834 636 - 1 4 5 6 ATÓM 455 ND1 HIS 57 -11,819 31.021 66411 1,000 4 0.52 Anisa 455 ND1 HIS 57 6021 5885 34 90 -1,360 1474 - 2 0 0 1 ATÓM 456 CE1 HIS 57 -10,798 31.410 67. 151 1,000 4 2.28 Anisa 456 CE1 HIS 57 6680 6066 3320 -1632 1099-1 7 7 2 ATÓM 457 NE2 HIS 57 -9,902 31.970 66362 1. 000 4 1.69 Anisa 457 NE2 HIS 57 6377 6133 3329 -1817 407 - 1 2 3 4 ATÓM 4 58 C HIS 57 -13,769 29.466 62547 1. 000 3 2 5 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33004

PCT / GB9S / 03860

- 105 -

ANISOU 453 C HIS 5 7 3083 5097 4 19 9 -29 1 7 ¾ 3 - 2 066 ATÓM 4 5 9 0 HIS 5 7 -14,902 29.965 62578 i. o o o, so Anisa 4 59 ABOUT HIS 57 3121 5097 4625 -731 1865 - 2565 ATÓM 4 ó 0 N GLY 58 -13,370 28.866 61432 1. 000 8.78 Anisa 460 N GLY 58 2841 4353 3742 -253 1341 -1506 ATÓM 461 C A GLY 58 -14,326 28.685 63332 1,000 2 6.99 Anisa 461 C A GLY 58 2471 3916 3869 24 1297 - 1 1 7 3 ATÓM 462 C GLY 58 -15,447 27.737 60738 1,000 9.94 Anisa 462 C GLY 58 2665 4357 4 3 53 - 2 ó 1 1323 -1058 ATÓM 463 ABOUT GLY 58 -15,241 26805 61. 5 3 4 1. 000 9.23 Anisa 463 ABOUT GLY 58 2976 4044 4 0 8 6 -571 1192 -1297 ATÓM 464 N SER 59 -16,635 27.958 60193 1,000 7.61 Anisa 464 N SER 59 2556 3905 4C29 -108 1461 - 1 6 7 6 ATÓM 4 6 5 C A SER 59 -17,812 27.153 60497 1,000 8.42 Anisa 465 C A SER 59 2675 4074 4049 -189 1293 - 1 3 2 5 ATÓM 4 6 6 CB SER 59 -19. 121 27.889 60162 1,000 8.29 Anisa 466 CB SER 59 2556 4574 3618 -339 1198 - 9 2 9 ATÓM 467 OC- SER 59 -19,229 27.978 58.739 1,000 8.66 Anisa 467 OG SER 59 3598 3742 3547 166 1729 - 8 6 6 ATÓM 468 C SER 59 -17,795 25.843 59.724 1,000 9.57 Anisa 468 C SER 59 3467 3990 37 79 -646 1462 - 1 2 0 7 ATÓM 469 ABOUT SER 59 -16,990 25.651 58.810 1,000 2 2.72 Anisa 469 ABOUT SER 59 3054 3042 2537 -144 648 - 3 7 9 ATÓM 470 N GLU 60 -18,698 24.939 60103 1,000 6.90 Anisa 470 N GLU 60 2413 3900 3907 -69 1079-8 5 3 ATÓM 471 CA GLU 60 -18,699 23.684 59359 1,000 6.98 Anisa 471 CA GLU 60 2699 3515 4037 -98 708 - 5 3 7 ATÓM 472 CB GLU 60 -19,646 22.681 60001 1,000 3 9.11 Anisa 472 CB GLU 60 5393 4393 5075 -1361 908 364 ATÓM 473 CG GLU 60 -19,011 21.665 60917 1,000 4 4.63 Anisa 473 CG GLU 60 5606 5,473 5878 -977 1078 1 2 1 9 ATÓM 474 CD GLU 60 -17,507 21.543 60797 1,000 8.52 Anisa 474 CD GLU 60 5714 6217 6503 -390 1208 8 7 7 ATÓM 475 OE1 GLU 60 -17,030 21.223 59.684 1,000 8.11 Anisa 475 OE1 GLU 60 5349 7545 5384 709 369 1 9 5 1 ATÓM 476 OE2 GLU 60 -16,828 21.763 61829 1,000 4 6.50 Anisa 476 OE2 GLU 60 4926 5742 7000 1158 1550 - 1 5 0 5 ATÓM 477 C GLU 60 -19,091 23.960 57915 1,000 2 5.30 Anisa 477 C GLU 60 2829 2728 4055 86,725 - 6 5 6 ATÓM 478 ABOUT GLU 60 -18,529 23.346 57.327 1,000 4.18 Anisa 478 ABOUT GLU 60 2119 2980 4091 -202 741-7 5 2 ATÓM 479 N ALA 61 -20,032 24.890 57.716 1,000 5.58 Anisa 479 N ALA 61 2083 3206 4432 -34 612 -774 ATÓM 480 CA ALA 61 -20,495 25.212 56.368 1,000 2 4.05 Anisa 480 CA ALA 61 1838 2999 4301 228 720 - 1 0 5 6 ATÓM 481 CB ALA 61 -21,670 26.176 56.459 1,000 7.53 Anisa 481 CB ALA 61 2807 1857 5797 394 704 - 6 0 7 ATÓM 482 C ALA 61 -19,385 25.790 55.500 1,000 7.31 Anisa 482 C ALA 61 3170 2572 4633 -377 1178 - 1 0 2 7 ATÓM 483 ABOUT ALA 61 -19,247 25.467 54.311 1. 000 2.29 Anisa 483 ABOUT ALA 61 2363 1876 4232 42 662 - 3 1 9 ATÓM 484 N GLU 62 -18,580 26.642 56.118 1,000 2.18 Anisa 484 N GLU 62 2075 2258 4094 396 569 - 3 8 4 ATÓM 485 C A GLU 62 -17,455 27.258 55.416 1,000 4.19 Anisa 485 C A GLU 62 2401 2603 4188 150 852-5 5 9 0 ATÓM 486 CB GLU 62 -16,806 28354 56.277 1. OOO 124.68 Anisa 486 CB GLU 62 2401 2490 4485 91 1272 - 8 2 8 ATÓM 487 CG GLU 62 -17,641 29.636 56356 1 .OOC 125.19 Anisa 487 CG GLU 62 2542 2620 4409 353 421-6 6 5 ATÓM 488 CD GLU 62 -17,288 30.581 57.480 1. . 000 2 9.2 7 Anisa 4 88 CD GLU 62 3284 2991 4845 621 515 -1290

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9SO3860

- 106 ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOMA ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM ANISOM ATOM

4S9

489

490

490

491

491

492

492

493

493

494

494

495

495

496

496

497

497

498

498

499

499

500

500

501

501

502

502

503

503

504

504

505

505

506

506

507

507

508

508

509

509

510

510

511

511

512

512

513

513

514

514

515

515

516

516

517

517

518

518

519

OEt GLU 62 -16,527 30241 58.410 1,000 3 0.11 OE1 GLU 62 3231 3067 5143 318 • Ira. »-1639 OE2 GLU 62 -17,796 31739 57436 1,000 3 5.30 OE2 GLU 62 4832 2994 5584 863 109 - 1 2 3 C GLU 62 -16,409 26.226 55.025 1,000 2 1.70 C GLU 62 2394 2421 3430 30 784 .-579 0 GLU 62 -15,818 26.218 53.940 1,000 19:44 0 GLU 62 2095 2140 3153 -301 466 - 6 0 4 N LYS 63 -16,184 25.308 55.972 1,000 2 0.08 N LYS 63 2472 2266 2893 -74 761-9 0 2 C A LYS 63 -15,246 24227 55678 1,000 19.73 C A LYS 63 2322 2559 2614 133 429-9 0 3 CB LYS 63 -14,934 23.497 56988 1,000 18:48 CB LYS 63 1803 2743 2476 -218 588 - 8 3 6 CG LYS 63 -13,946 24.240 57.881 1,000 19:17 CG LYS 63 2115 2332 2836 -296 325-6 6 4 CD LYS 63 -13,839 23.651 59.290 1,000 6.23 CD LYS 63 2978 4084 2902 -888 -177-2 8 7 CE LYS 63 -12,753 24.383 60068 1,000 7.75 CE LYS 63 3074 5008 2461 -1239 500 - 1 0 8 1 NZ LYS 63 -12,929 24.378 61530 1,000 3 4.95 NZ LYS 63 3177 7579 2524 -2,594 840-8 9 4 C LYS 63 -15,789 23.304 54586 1,000 17:52 C LYS 63 2014 2191 2453 51 529 '-691 0 LYS 63 -15,025 22.953 53.654 1,000 17:58 0 LYS 63 2266 1709 2704 158 706 - 6 5 3 N ARG 64 -17,069 22.912 54641 1,000 19.63 N ARG 64 2081 2452 2926 -14 614 -5 92 CA ARG 64 -17,618 22.041 53595 1,000 19:00 CA ARG 64 1509 2526 3185 -3 620 - 6 5 2 C ARG 64 -17,471 22.634 52194 1,000 2 0.42 C ARG 64 2165 2436 3157 -390 -22- 5 3 6 0 ARG 64 -17,204 21.934 51195 1,000 18.83 0 ARG 64 1854 2184 3115 -434 574 - 2 0 1 CB ARG 64 -19,080 21.670 53.871 1,000 2 4.70 CB ARG 64 1470 3652 4263 -51 841 - 9 0 8 CG ARG 64 -19,838 20.933 52.795 1,000 6.49 CG ARG 64 2961 5284 5621 -2020 138-8 8 2 CD ARG 64 -21,315 20645 53.095 1,000 6.32 CD ARG 64 3034 6962 7603 -2,438 327-1 1 8 7 NE ARG 64 -21,776 21216 54.331 1,000 55.81 NE ARG 64 3917 8636 8652 -3960 2222 - 1 7 8 0 CZ ARG 64 -22,814 21.840 54811 1,000 58.82 CZ ARG 64 4438 8939 8972 -3,479 1988 - 2 4 8 1 NH1 ARG 64 -23,884 22.106 54.071 1,000 76.83 NH1 ARG 64 6024 9527 13641 -1787 -165-1 8 7 2 NH2 ARG 64 -22,797 22.213 56093 1,000 69.53 NH2 ARG 64 7792 9201 9424 -5,884 3891 - 3 3 0 5 N ALA 65 -17.621 23.947 52.066 1,000 2 0.43 N ALA 65 1689 2554 3519 24 613 - 5 2 5 C A ALA 65 -17,505 24.6S6 50.782 1,000 19:45 CA ALA 65 1649 2216 3523 409 185 - 5 5 3 CB ALA 65 -17,912 26.108 50984 1,000 2 3.73 CB ALA 65 1420 2019 5579 126 -373-7 4 2 C ALA 65 -16,118 24.549 50.168 1,000 17.89 C ALA 65 152 4 2099 3173 -47 108 - 1 0 0 0 ALA 65 -15,983 24.732 48.954 1,000 18.77 0 ALA 65 1830 2178 3123 122 - 8 - 2 2 9 N VAL 66 -15,100 24.248 50.973 1,000 17.99 N VAL 66 1547 2151 3137 -86 36 - 1 9 7 C A VAL 66 -13,746 24.066 50.430 1,000 16.74

SUBSTITUTE SHEET (RULE 26)

WO 9403904 VAL 6 ó 15 5 3 - 107 - 1S59 2 348 PCT / GH9S / 03860 ANISO'J 519 C A -62 - 5 º-254 ATÓM □ 2 0 C 3 VAL 66 -12,775 25 151 5.3. 9 5 1 1. 000 ISL., 2 9 Anisa 520 C Ξ VAL 66 1805 1804 2963 -330 33S-1 8 5 ATÓM 521 CGL VAL 66 -13,238 26.532 50.455 1-. 000 16.70 Anisa 521 CG1 VAL 6 6 1547 1800 29 97 111 55 5 - 5 5 3 ATÓM 522 CG2 VAL 66 -12,652 25.180 52462 1. 000 18.65 Anisa 522 CG2 VAL 66 2053 1995 3C 36 -193 17 - 6 3 8 ATÓM 523 C VAL 6 6 -13 .201 22.680 5C.724 1,000 15.66 Anisa 523 C VAL 66 1775 1813 2362 -70 -250 - 4 5 6 ATÓM 524 ABOUT VAL 66 -11. 972 22.493 50.808 1,000 14:19 Anisa 524 ABOUT VAL 66 1747 157 6 2069 -122 -56 - 3 4 6 ATÓM 525 N THR 67 -14,071 21.695 50.873 1,000 14:46 Anisa 525 N THR 67 1550 1602 2343 126 -48-7 2 2 ATÓM 526 C A THR 67 -13,723 20.279 51.000 1,000 6.14 Anisa 526 C A THR 67 1461 1698 2185 234 5 - 7 3 0 ATÓM 527 CB THR 67 -14. 419 19.647 52.225 1,000 8.15 Anisa 527 CB THR 67 1721 1955 20 53 -51 -426 4 4 4 ATÓM 528 OG1 THR 67 -14,089 20.337 53.453 1,000 17:41 Anisa 528 OG1 THR 67 2538 1949 2128 -39 70-7 1 6 ATÓM 529 CG2 THR 67 -13,915 18.215 52. 420 1,000 16.63 Anisa 529 CG2 THR 67 2182 1888 2248 148 293 - 6 6 8 ATÓM 530 C THR 67 -14,067 19-518 49.728 1,000 12:37 Anisa 530 C THR 67 1144 1422 2132 209 -95-5 5 1 7 ATÓM 531 ABOUT THR 67 -15,208 19.567 49.229 1,000 14.82 Anisa 531 ABOUT THR 67 1197 2086 2350 208 -168- 3 6 2 ATÓM 532 N SER 68 -13,092 18.790 49.180 1,000 11.61 Anisa 532 N SER 68 1109 1421 1881 37 -58 - 5 3 4 ATÓM 533 CA SER 68 -13,306 17.955 48.003 1,000 11:45 Anisa 533 CA SER 68 1274 1444 1631 -49 -30-3 3 7 4 ATÓM 534 CB SER 68 -12,027 17317 47.480 1,000 11.88 Anisa 534 CB SER 68 1446 1523 1544 79 252 -157 ATÓM 535 OG SER 68 -11,026 18.292 47.239 1,000 16.95 Anisa 535 OG SER 68 1557 2314 2569 -336 389 - 2 0 8 ATÓM 536 C SER 68 -14,269 16.815 48.319 1,000 11:56 Anisa 536 C SER 68 1287 1375 1732 -61 53 - 4 0 7 ATÓM 537 ABOUT SER 68 -14,308 16.384 49. 476 1,000 14.62 Anisa 537 ABOUT SER 68 1998 1860 1697 -538 153 - 4 4 0 ATÓM 538 N PRO 69 -15,026 16.324 47.344 1,000 12.78 Anisa 538 N PRO 69 1476 1473 1905 -243 - 88 - 1 9 4 ATÓM 539 CD PRO 69 -15,130 16.801 45.953 1,000 12:47 Anisa 539 CD PRO 69 1022 1808 1909 -199 -203 - 1 4 4 ATÓM 540 CA PRO 69 -15,941 15214 47639 1,000 12:21 Anisa 540 CA PRO 69 1358 1369 1913 -178 148 - 4 4 7 ATÓM 541 CB PRO 69 -16,825 15.193 46.355 1,000 13.94 Anisa 541 CB PRO 69 1362 1591 2343 -251 -178-1 ATÓM 542 CG PRO 69 -15,924 15.715 45.290 1,000 14:38 Anisa 542 CG PRO 69 1396 1947 2122 -554 -511 178 ATÓM 543 C PRO 69 -15,270 13.882 47.S 12 1,000 13:25 Anisa 543 C PRO 69 1206 1526 2303 -217 -115 -10 0 ATÓM 544 ABOUT PRO 69 -15,932 12.985 48.481 1,000 1.14 Anisa 544 ABOUT PRO 69 1753 1450 2122 -373 100 - 3 0 1 ATÓM 545 N VAL 70 -14,015 13.692 47.554 1,000 13:46 Anisa 545 N VAL 70 1288 1479 2348 -174 -108 - 2 7 5 ATÓM 546 CA VAL 70 -13. 184 12.548 47.898 1,000 13:49 Anisa 546 CA VAL 70 1404 1692 2030 37 138-1 9 5 ATÓM 547 CB VAL 70 -12,587 11.720 46737 1,000 16:39 Anisa 547 CB VAL 70 2142 1648 2439 -225 613 - 4 5 2 ATÓM 548 CGL VAL 70 -13,615 10.756 46.208 1,000 3 3.50 Anisa 548 CGL VAL 70 6470 2984 3274 -2,702 41-8 6 7 ATÓM 549 CG2 VAL 70 -11,995 12.613 45.640 1. 000 16:46 · AJ! I SOU 54 9 CG2 VAL 70 1749 2234 2273 269 444 2 3

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S / 03860

-108- ATÓM 550 C VAL 70 -12,042 13.057 48.782 1,000 13:59 Anisa 550 C VAL 70 1618 1382 2163 -38 -ΙΛ, Ι 12 7 ATÓM 551 ABOUT VAL 70 -11,426 14.105 48.493 1,000 14:20 Anisa 551 ABOUT VAL 70 1748 1685 1964 -2 6 5 26182 ATÓM 552 N PRO 71 -11,786 12.365 49.898 1,000 14:21 Anisa 552 N PRO 71 1607 1507 2285 -115 -62 310 ATÓM 553 CD PRO 71 -12,432 11.125 50.378 1,000 14.70 Anisa 553 CD PRO 71 1920 1590 2076 -201 646 4 ATÓM 554 CA PRO 71 -10,830 12.919 50.878 1,000 17:41 Anisa 554 CA PRO 71 2429 2008 2178 -522 -342 418 ATÓM 555 CB PRO 71 -11,338 12.304 52.193 1,000 2 0.87 Anisa 555 CB PRO 71 3768 2082 2081 -743 190 14 ATÓM 556 CG PRO 71 -11,908 10.989 51.775 1,000 18:28 Anisa 556 CG PRO 71 3534 1665 1746 -338 785 - 5 4 ATÓM 557 C PRO 71 -9,384 12.543 50.619 1,000 17:14 Anisa 557 C PRO 71 2183 2304 2026 -684 -816 4 4 ATÓM 558 0 PRO 71 -8,730 11.796 51.330 1,000 2 0.54 Anisa 558 0 PRO 71 2745 2610 2448 -87 -404 414 ATÓM 559 N THR 72 -8,834 13.111 49.556 1,000 16:59 Anisa 559 N THR 72 2156 2046 2103 -235 -508-1 7 ATÓM 560 CA THR 72 -7,496 12.818 49.090 1,000 17:43 Anisa 560 CA THR 72 2113 1884 2626 -254 -510-2 8 8 ATÓM 561 CB THR 72 -7,477 12.829 47545 1,000 15.98 Anisa 561 CB THR 72 1700 1761 2611 211 -458-4 4 2 1 ATÓM 562 OG1 THR 72 -8,027 14.094 47.128 1,000 17:28 Anisa 562 OG1 THR 72 2146 1553 2868 27 -355-2 2 7 1 ATÓM 563 CG2 THR 72 -8,348 11.764 46.929 1,000 12.63 Anisa 563 CG2 THR 72 1296 1581 1923 -46 327 - 1 2 7 ATÓM 564 C THR 72 -6,418 13.805 49.549 1,000 17.83 Anisa 564 C THR 72 2153 1773 2847 -155 -1228 232 ATÓM 565 0 THR 72 -5,216 13.536 49.329 1,000 2 0.17 Anisa 565 0 THR 72 2142 2265 3257 -225 -1049 480 ATÓM 566 N MET 73 -6,785 14.920 50.169 1,000 19:43 Anisa 566 N MET 73 2876 2052 2455 -782 -451-1 1 4 4 ATÓM 567 CA MET 73 -5,799 15.944 50521 1,000 18.75 Anisa 567 CA MET ‘73 2117 2326 2682 -538 -466 - 2 7 0 ATÓM 568 CB MET 73 -4,758 15.338 51.480 1,000 3.22 Anisa 568 CB MET 73 1826 2825 3718 -377 -306 595 ATÓM 569 CG MET 73 -5,374 15.059 52.843 1,000 27.01 Anisa 569 CG MET 73 3545 2853 3864 -84 -88 1 5 2 6 ATÓM 570 SD MET 73 -4,107 14.850 54.107 1,000 2.23 Anisa 570 SD MET 73 4364 4245 3637 469 -400 583 ATÓM 571 CE MET 73 -3,179 13.492 53.374 1,000 6.74 Anisa 571 CE MET 73 2885 4895 2381 326 429 1 3 4 8 ATÓM 572 C MET 73 -5,066 16.582 49355 1,000 17:20 Anisa 572 C MET 73 1338 2129 3067 -20 -269 - 1 7 4 ATÓM 573 0 MET 73 -3,945 17.110 49.498 1,000 2 1.20 Anisa 573 0 MET 73 1713 2512 3832 -541 51-10 10 4 ATÓM 574 N ARG 74 -5,630 16.600 48.175 1,000 18.64 Anisa 574 N ARG 74 1881 2051 3150 84 -461,543 ATÓM 575 CA ARG 74 -5,091 17.180 46.967 1,000 15.73 Anisa 575 CA ARG 74 937 1986 3053 169 27 - 1 6 4 ATÓM 576 CB ARG 74 -5,655 16.537 45.704 1,000 16:53 Anisa 576 CB ARG 74 1711 1434 3137 -263 142 -16 0 ATÓM 577 CG ARG 74 -4,911 16.934 44.440 1,000 1.15 Anisa 577 CG ARG 74 1270 1288 3144 -156 279 - 5 6 4 ATÓM 578 CD ARG 74 -5,683 16.543 43.185 1,000 16:10 Anisa 578 CD ARG 74 1967 1031 3120 268 -92 - 4 0 6 ATÓM 579 NE ARG 74 -4,902 16.816 41.966 1. 000 18.81 Anisa 579 NE ARG 74 2259 1813 3075 -432 -252-2 9 6 ATÓM 580 CZ ARG 74 -5,033 17.824 41.130 1. 000 16.64

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98O3800

- 109 -

Anisa 580 CZ ARG 74 1968 16 4 6 270 9 - 1 4 1 - 190 -595 ATÓM 581 NH1 ARG 74 -5,951 18.775 4. 2 9 3 1. 000 ^, 09 Anisa 581 NH1 ARG 74 1899 2075 3 6 5 0 54-353-7 8 8 ATÓM 582 NH2 ARG 74 -4,220 17.896 4 0.0 N i. 000 2 0.1 2 Anisa 582 NH2 ARG 74 2366 2844 24 37 153 -196-400 ATÓM 583 C ARG 74 -5,373 18.681 4 é. 9 ô 5 1,000 1 2.7 0 Anisa 583 C ARG 74 1187 1880 1756 6 -22-136 ATÓM 584 ABOUT ARG 74 -4. 501 19.465 46.582 1,000 1 4.0 7 Anisa 584 ABOUT ARG 74 1049 2048 2247 -221 -170 -480 ATÓM 585 N ARG 75 -6 .567 19.099 47.387 1. 000 1 2.7 2 Anisa 585 N ARG 75 1402 1702 1728 95,182 -103 ATÓM 586 C A ARG 75 -7,006 20.471 47.308 1 · 000 1 3.4 Anisa 586 C A ARG 75 1924 1618 1548 87 275-1 9 3 ATÓM 587 CB ARG 75 -7,737 20.784 45.995 1.000 1 3.4 5 Anisa 587 CB ARG 75 1972 1387 1751 -179 51 -9 ATÓM 588 CG ARG 75 -6,908 20.637 44.721 1,000 1 3.3 8 Anisa 588 CG ARG 75 1638 1851 1594 78 -217 ATÓM 589 CD ARG 75 -5 .849 21.708 44.582 1,000 1 2.8 5 Anisa 589 CD ARG 75 1537 1602 1741 238 62 - 1 5 ATÓM 590 NE ARG 75 -5,087 21.685 43.347 1,000 1 3.7 1 Anisa 590 NE ARG 75 1708 1797 17 05 188 90-9 1 ATÓM 591 CZ ARG 75 -3. 984 21.036 43 013 1.000 1 2.4 6 Anisa 591 CZ ARG 75 1348 1656 1731 -89 87 1 1 7 ATÓM 592 NH1 ARG 75 -3,418 20.241 43.894 1,000 1 4.6 4 Anisa 592 NH1 ARG 75 1933 1794 1834 186 -92 6 5 ATÓM 593 NH2 ARG 75 -3,444 21.167 41.794 1.000 13.72 Anisa 593 NH2 ARG 75 1510 2037 1667 -136 84-8 3 ATÓM 594 C ARG 75 -7,948 20.787 48.475 1.000 12.74 Anisa 594 C ARG 75 1400 1656 1784 -209 214- 4 6 4 ATÓM 595 ABOUT ARG 75 -8,780 19.944 48.818 1.000 14.6 0 Anisa 595 ABOUT ARG 75 1348 1926 2273 -427 156 - 4 8 0 ATÓM 596 N GLY 76 -7,830 21.955 49078 1,000 11.9 2 Anisa 596 N GLY 76 1268 1537 1724 -22 34- 3 8 9 ATÓM 597 CA GLY 76 -8,801 22.395 50.070 1,000 1 2.4 4 Anisa 597 CA GLY 76 1439 1493 1796 -315 263 - 4 1 2 ATÓM 598 C GLY 76 -8,536 21.857 51469 1.000 1 2. 5 0 Anisa 598 C GLY 76 1324 1527 1900 5 326 - 2 7 4 ATÓM 599 ABOUT GLY 76 -7,388 21.517 51.769 1,000 14.2 5 Anisa 599 ABOUT GLY 76 1100 2099 2218 (-277) 239 - 2 2 5 ATÓM 600 N PHE 77 -9,574 21.840 52.287 1,000 1 2.6 5 Anisa 600 N PHE 77 1191 1806 1809 - 162 231 - 3 5 1 ATÓM 601 CA PHE 77 -9,526 21.474 53.594 1.000 14.0 0 Anisa 601 CA PHE 77 1295 2110 1914 (260) 276 - 1 3 8 ATÓM 602 CB PHE 77 -10,644 22.226 54.451 1,000 14.7 3 Anisa 602 CB PHE 77 1554 2169 1874 -402 485 - 3 1 6 ATÓM 603 CG PHE 77 -10,773 21.824 55.912 1.00017.13 Anisa 603 CG PHE 77 1927 2730 1849 -374,378 - 2 4 3 ATÓM 604 CD1 PHE 77 -9,949 22.369 56886 1.000 1 9.4 9 Anisa 604 CD1 PHE 77 2744 2700 19 62 -119 219-7 8 9 ATÓM 605 CD2 PHE 77 -11,730 20.902 56.309 1,000 1 9.1 3 Anisa 605 CD2 PHE 77 2348 3068 1852 -501 864 1 6 5 ATÓM 606 CE1 PHE 77 -10,068 21.973 58.217 1,000 1 9.7 5 Anisa 606 CE1 PHE 77 2956 2381 2168 -174 -313 - 3 4 0 ATÓM 607 CE2 PHE 77 -11,829 20.479 57.627 1,000 1 8.7 3 Anisa 607 CE2 PHE 77 2565 2711 1841 -382 310 - 7 6 ATÓM 608 CZ PHE 77 -10,986 21.013 58.S84 1.000 19.22 Anisa 608 CZ PHE 77 2378 2542 2382 97 13 - 3 6 4 ATÓM 609 C PHE 77 -9,668 19.976 53.S 24 1,000 1 3.7 3 Anisa 609 C PHE 77 1306 2096 1813 -368 2 1 - 2 0 3 ATÓM 610 ABOUT PHE 77 -10,520 19.313 53.291 1. 000 1 6.0 2 Anisa 610 ABOUT PHE 77 1386 2508 2194 -470-127 4 4 5

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S'03860

- 110 -

ATÓM ô 11 N THR 76 -8,869 19.439 = 4.852 1,000 14:33 Anisa 611 N THR 78 1543 2270 1629 -472 -33, -4 9 ATÓM 612 C A THR 78 -9,034 18.053 55.276 1,000 15.80 Anisa 612 C A THR 78 1813 2310 1880 = 508 -23 8 2 ATÓM 613 CB THR 78 -8,001 17.081 54.666 1,000 13:26 Anisa 613 C5 THR 78 1583 2199 3158 -599 33-1 13 1 ATÓM 614 OG1 THR 78 -7,924 17.323 53.266 1,000 2 1.81 Anisa 614 OG1 THR 78 3 351 1877 3057 -88 94 3 - 3 6 0 ATÓM 615 CG2 THR 78 -8,419 15.634 54888 1,000 2 0.35 Anisa 615 CG2 THR 78 2855 2254 2622 -1119 1108 - 7 0 8 ATÓM 616 C THR 78 -8,832 17,881 56.777 1,000 19:14 Anisa 616 C THR 78 2845 2479 1948 -1747 -471 169 ATÓM 617 ABOUT THR 78 -7,801 18.311 57.290 1,000 4.22 Anisa 617 ABOUT THR 78 2781 2889 2704 -1718 -985 763 ATÓM 618 N GLY 79 -9,730 17.203 57.484 1,000 19:20 Anisa 618 N GLY 79 2629 2823 1844 -1352 19 4 5 ATÓM 619 CA GLY 79 -9,429 16.695 58819 1,000 16.69 Anisa 619 C A GLY 79 1800 2770 1771 -518 196-9 5 ATÓM 620 C GLY 79 -8,672 15.376 58.720 1,000 2 2.98 Anisa 620 C GLY 79 2381 2874 3477 -272 -289 - 5 4 ATÓM 621 ABOUT GLY 79 -9,227 14.504 58.044 1,000 5.57 Anisa 621 ABOUT GLY 79 3683 2520 3514 -456 - 974 - 1 4 1 ATÓM 622 N LEU 80 -7,494 15.236 59.319 1,000 2 2.91 Anisa 622 N LEU 80 2412 2900 3392 -206 - 6 0 6 ATÓM 623 CA LEU 80 -6,644 14.081 59.072 1,000 2 5.08 Anisa 623 CA LEU 80 2848 2777 3904 206 621 361 ATÓM 624 C LEU 80 -6,372 13.294 60370 1,000 4.30 Anisa 624 C LEU 80 2834 2762 3637 -300 480 200 ATÓM 625 ABOUT LEU 80 -5,729 13.812 61291 1,000 5.14 Anisa 625 ABOUT LEU 80 2253 3017 4283 27 145 > - 5 ATÓM 626 CB LEU 80 -5,318 14.480 58.415 1,000 7.16 Anisa 626 CB LEU 80 3057 3326 3937 379 918 641 ATÓM 627 CG LEU 80 -4,411 13.338 57.933 1,000 9.43 Anisa 627 CG LEU 80 3474 3505 4204 287 1260 173 ATÓM 628 CD1 LEU 80 -5,145 12.438 56.956 1,000 8.31 Anisa 628 CD1 LEU 80 5673 3891 4993 -1554 1987 - 2 7 7 ATÓM 629 CD2 LEU 80 -3,137 13.884 57306 1,000 2 9.85 Anisa 629 CD2 LEU 80 3502 3919 3920 125 1307 - 2 7 4 ATÓM 630 N GLU 81 -6,853 12.055 60396 1,000 5.58 Anisa 630 N GLU 81 2469 2759 4490 -196 -82 510 ATÓM 631 CA GLU 81 -6,739 11.038 61415 1,000 2 5.98 Anisa 631 CA GLU 81 2739 2692 4441 -258 -55 424 ATÓM 632 C GLU 81 -5,299 10.536 61562 1,000 6.28 Anisa 632 C GLU 81 2870 3268 3848 187 407 841 ATÓM 633 ABOUT GLU 81 -4,489 10.655 60655 1,000 2 8.19 Anisa 633 ABOUT GLU 81 3709 3520 3483 253 799-5 5 4 4 ATÓM 634 CB GLU 81 -7,685 9.861 61123 1,000 2 9.83 Anisa 634 CB GLU 81 3533 2894 4906 -770 270 181 ATÓM 635 CG GLU 81 -7,241 8832 60098 1,000 5.34 Anisa 635 CG GLU 81 1737 2915 4976 284 -1220 158 ATÓM 636 CD GLU 81 -7,568 9156 58.649 1,000 2 7.00 Anisa 636 CD GLU 81 1841 3405 5012 475 -1887 - 4 ATÓM 637 OE1 GLU 81 -8,120 10.240 58.324 1,000 8.81 Anisa 637 OE1 GLU 81 3444 3091 4413 322 -156 7 9 1 ATÓM 638 OE2 GLU 81 -7,240 8.273 57814 1,000 3 1.31 Anisa 638 OE2 GLU 81 3514 3384 4999 162 352 100 ATÓM 639 N SER 82 -4,988 9.974 62.720 1,000 3 1.00 Anisa 639 N SER 82 3568 3780 4430 -65 -31 1 4 8 4 ATÓM 640 CA SER 82 -3,653 9.422 62 .959 1. 000 3 0.29 Anisa 640 C.A. SER 82 3692 3278 4540 -157 -515 10 11 Z, TOM 64 1 C SER 8 2 -3 421 8.150 62. 150 1. 000 3 1.76

SUBSTTTirnZ SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

ANISOU 641 C SER 82 3995 - 111 - 3241 4831 -102 -1104 847 ATÓM 642 ABOUT SER 82 -4 .313 7728 61397 1,000 i-1.0 1 Anisa 642 ABOUT SER 82 3193 3794 5935 458 -1188 134 ATÓM 643 CB SER 82 -3,463 9.167 64452 1,000 3 4.74 Anisa 643 CB SER 82 4687 3907 4 306 -232 -979 971 ATÓM 644 OG SER 82 -2,360 8.305 64681 1,000 4 1.53 Anisa 644 OG SER 82 4922 5366 5490 236 -1958 970 ATÓM 645 N GLY 91 -17,230 9498 70136 1,000 42.64 Anisa 645 N GLY 91 4516 7599 4 08 6 -2,166 2340 - 4 ATÓM 646 CA GLY 91 -17,485 10.892 69789 1,000 44.91 Anisa 646 CA GLY 91 6666 7702 2697 -4311 -1561 565 ATÓM 647 C GLY 91 -16,227 11.662 69452 1,000 38.67 Anisa 647 C GLY 91 5455 7587 1652 -2,821 -274 - 1 6 9 ATÓM 648 ABOUT GLY 91 -15,164 11.480 70.040 1,000 3 2.45 Anisa 648 ABOUT GLY 91 4241 4474 3616 -183 1152 - 3 4 9 ATÓM 649 N GLY 92 -16,332 12.558 68474 1,000 3 1.97 Anisa 649 N GLY 92 3881 5904 2363 -1382 735 - 5 6 1 ATÓM 650 CA GLY 92 -15,232 13.412 68075 1,000 33.02 Anisa 650 C A GLY 92 4121 6150 2274 -1716 851-9 5 6 ATÓM 651 C GLY 92 -15,223 13.696 66572 1,000 6.22 Anisa 651 C GLY 92 2603 5046 2314 -885 741-9 4 7 ATÓM 652 ABOUT GLY 92 -16,289 13.666 65939 1,000 2 3.91 Anisa 652 ABOUT GLY 92 2490 3396 3198 -680 547 - 5 6 7 ATÓM 653 N SER 93 -14,010 13.956 66088 1,000 2 3.77 Anisa 653 N SER 93 2405 3917 2708 -372 736 - 5 7 0 ATÓM 654 CA SER 93 -13,801 14.287 64.690 1,000 23:41 Anisa 654 CA SER 93 2700 3292 2901 -386 970-9 9 9 ATÓM 655 C SER 93 -12,410 13.852 64.240 1,000 24.26 Anisa 655 C SER 93 2547 3908 2763 -286 834 - 2 2 4 ATÓM 656 ABOUT SER 93 -11,497 13.831 65089 1,000 27.06 Anisa 656 ABOUT SER 93 3401 3536 3346 630 92 - 3 7 6 ATÓM 657 CB SER 93 -13,966 15.795 64467 1,000 25.71 Anisa 657 CB SER 93 2811 3225 3735 -576 271 - 5 0 7 ATÓM 658 OG SER 93 -13,558 16.158 63.150 1,000 28.14 Anisa 658 OG SER 93 2694 3713 4284 -373 291 5 1 7 ATÓM 659 N TYR 94 -12,254 13.533 62949 1,000 24.24 Anisa 659 N TYR 94 2786 3320 3104 -204 791-8 1 7 ATÓM 660 CA TYR 94 -10,878 13.262 62498 1,000 23.94 Anisa 660 CA TYR 94 3089 2502 3505 95 1111 - 6 8 3 ATÓM 661 C TYR 94 -10,017 14.531 62584 1,000 25.19 Anisa 661 C TYR 94 2601 2657 4312 147 736 - 6 2 5 ATÓM 662 ABOUT TYR 94 -8,786 14.421 62694 1,000 30.11 Anisa 662 ABOUT TYR 94 2617 3095 5726 307 760 3 7 ATÓM 663 CB TYR 94 -10,800 12.659 61098 1,000 25.64 Anisa 663 CB TYR 94 3566 2910 3267 -293 1330 - 5 2 5 ATÓM 664 CG TYR 94 -11,600 11.410 60876 1,000 23:22 Anisa 664 CG TYR 94 3359 2768 2697 -69 784 - 2 6 4 ATÓM 665 CD1 TYR 94 -12,451 11.455 59777 1,000 26.01 Anisa 665 CD1 TYR 94 4410 2730 2741 499 354 - 5 4 3 ATÓM 666 CD2 TYR 94 -11,564 10.252 61635 1,000 24.42 Anisa 666 CD2 TYR 94 3117 2866 3297 73,458 - 1 4 ATÓM 667 CE1 TYR 94 -13,243 10.407 59.443 1,000 8.75 Anisa 667 CE1 TYR 94 4559 3328 3037 434 140 - 13 7 0 ATÓM 668 CE2 TYR 94 -12,375 9159 61.305 1,000 6.47 Anisa 668 CE2 TYR 94 4707 2585 2764 -220 1227 - 7 0 8 ATÓM 669 CZ TYR 94 -13,209 9247 60.212 1.00ct l 9.70 Anisa 669 CZ TYR 94 5641 3518 2125 -1172 ! 1103-14 14 7 ATÓM 670 OH TYR 94 -14,059 8.281 59.730 1.00ct 134.02 Anisa 670 OH TYR 94 3079 3962 5886 -423 1593 - 2 5 3 8 ATÓM 671 N SER 95 -10,628 15.714 62561 1,000 2 2.6 1 Anisa 671 N SER 95 2460 2497 3632 -54 58 - 3 3 8

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-112-

ATÓM 672 C A SER 95 -9,924 16.975 62.750 1.000 22.54 Anisa 672 C A SER 95 2257 2603 3706 -120 4 6 ATÓM 673 C SER 95 -9,370 17.106 64163 1.000 23.5 8 Anisa 673 C SER 95 1811 3478 3671 - 521 -88 - 8 5 ATÓM 674 0 SER 95 -8,623 18.034 64481 1,000 2 6.5 3 Anisa 674 0 SER 95 2592 3242 4247 -469 -167 6 6 1 ATÓM 675 CB SER 95 -10,838 18.177 62478 1.000 27.5 8 Anisa 675 CB SER 95 3657 2556 4264 365 -378 2 8 ATÓM 676 OG SER 95 -11,506 18.093 61242 1,000 3 9.4 0 Anisa 676 OG SER 95 6336 4214 4421 900 - 1445 1 4 4 2 ATÓM 677 N ASP 96 -9,712 16.194 65060 1,000 2 5.0 4 Anisa 677 N ASP 96 2579 3688 3248 -399 277 2 3 2 ATÓM 678 C A ASP 96 -9,228 16317 66422 1.000 2 4.4 2 Anisa 678 CA ASP 96 2603 3347 3330 -470 257-5 5 6 ATÓM 679 C ASP 96 -7,735 16.050 66501 1.000 24.45 Anisa 679 C ASP 96 2597 3228 3466 - 471 162 - 3 8 3 ATÓM 680 0 ASP 96 -7,073 16.589 67404 1.000 26.5 1 Anisa 680 0 ASP 96 2656 4047 3370 -170 160-7 9 8 ATÓM 681 CB ASP 96 -9,952 15.334 67334 1.000 24.9 7 Anisa 681 CB ASP 96 2310 3806 3371 -423 -228 7 7 ATÓM 682 CG ASP 96 -11,411 15.605 67606 1.000 26.77 Anisa 682 CG ASP 96 2272 4334 3566 -362 -240 7 1 7 ATÓM 683 ODL ASP 96 -11,935 16.723 67388 1.000 33.94 Anisa 683 OD1 ASP 96 3267 4894 4733 646 204 5 6 9 ATÓM 684 OD2 ASP 96 -12,058 14.646 68083 1.000 32. 65 Anisa 684 OD2 ASP 96 3624 4709 4072 -1032 1446 - 02 ATÓM 685 N TYR 97 -7,254 15.226 65581 1.000 22.21 Anisa 685 N TYR 97 2292 3389 2760 -376 -77 - 02 ATÓM 686 CA TYR 97 -5,835 14.852 65583 1.000 23.71 Anisa 686 CA TYR 97 2480 3542 2987 -27 105 6 4 4 ATÓM 687 C TYR 97 -5,026 15.828 64743 1.000 23.06 Anisa 687 C TYR 97 2363 3754 2647 -410 -78 3 5 0 ATÓM 688 0 TYR 97 -3,992 16.327 65230 1.000 24.2 9 Anisa 688 0 TYR 97 2205 3845 3178 -133 -230 7 5 ATÓM 689 CB TYR 97 -5,585 13.451 65035 1.000 28.38 Anisa 689 CB TYR 97 3230 3324 4229 540 -450 8 3 2 ATÓM 690 CG TYR 97 -4,132 13.025 65082 1.000 30.37 Anisa 690 CG TYR 97 3278. 4101 4161 767 -191 6 7 1 ATÓM 691 CD1 TYR 97 -3Í511 12.691 66285 1.000 30.1 9 Anisa 691 CD1 TYR 97 2878 4475 4119 1105 151 9 5 1 ATÓM 692 CD2 TYR 97 -3,370 12.945 63922 1.000 29.79 Anisa 692 CD2 TYR 97 3317 4005 3997 -253 5 4 4 ATÓM 693 CE1 TYR 97 -2,178 12.294 66324 1.000 32.77 Anisa 693 CE1 TYR 97 2554 4771 5126 576 -68 7 6 3 ATÓM 694 CE2 TYR 97 -2,043 12.553 63955 1.000 32.68 Anisa 694 CE2 TYR 97 3536 3793 5087 403,353 3 2 3 ATÓM 695 CZ TYR 97 -1,445 12.228 65157 1.000 3 3. 00 Anisa 695 CZ TYR 97 2633 4284 5622 1067 264 4 5 6 ATÓM 696 OH TYR 97 -0,121 11.845 65156 1.000 42.66 Anisa 696 OH TYR 97 2572 5373 8264 1160 764 1 2 7 7 ATÓM 697 CB SER 98 -3,465 16.575 62134 1.000 2 3. 20 Anisa 697 CB SER 98 2461 2766 3587 105 2 - 5 4 5 ATÓM 698 OG SER 98 -3,632 15.649 61078 1,000 2 6.4 9 Anisa 698 OG SER 98 3824 3059 3180 -154 238 - 57 ATÓM 699 C SER 98 -5,694 17.744 61701 1.00018.66 Anisa 699 C SER 98 2301 2150 2637 -296 66 1 3 ATÓM 700 0 SER 98 -6,768 17.212 61413 1,000 2 0.88 Anisa 700 0 SER 98 3042 2245 2646 -945 -249 1 8 1 ATÓM 701 N SER 98 -5,457 16.110 63511 1.000 23.62 Anisa 701 N SER 98 2816 3227 2931 -441 -396 6 0 5 ATÓM 702 CA SER 98 -4,748 17.143 62741 1,000 2 1.3 1

SUBSTITUTE SHEET (RULE 25)

WO 99/33994

PCT / GB98 / 03860

-113-

Anisa 702 CA SER 98 2430 2687 2982 132 153 2 9 4 ATÓM 703 N MET 99 -5,307 18.891 61148 1.000 1Λ., У8 Anisa 703 N MET 99 2392 2722 1984 -978 -366 1 0 0 ATÓM 704 CA MET 99 -6,047 19.560 60075 h. 000 1 7.84 Anisa 704 CA MET 99 2431 2620 1726 -945 -212 - 17 ATÓM 705 CB MET 99 -6,819 20.779 60.585 1,000 1 9.7 1 Anisa 705 CB MET 99 2348 2968 2173 -678 25 6 4 ATÓM 706 CG MET 99 -8,052 20.392 61374 1.000 2 3. 6 8 Anisa 706 CG MET 99 2360 3055 35B2 -504,393 4 8 9 ATÓM 707 SD MET 99 -9,031 21.821 61911 1.000 22.33 Anisa 707 SD MET 99 2569 3383 2534 -522 170 - 1 2 0 ATÓM 708 CE MET 99 -8,148 22.225 63419 1,000 3 6.9 8 Anisa 708 CE MET 99 6485 4165 3401 -225 -1904-2 ATÓM 709 C MET 99 -5,070 19.954 58973 1.000 17.19 Anisa 709 C MET 99 2269 2488 1776 -960 -194 - 2 0 0 ATÓM 710 0 MET 99 -3,964 20.341 59324 1.00016.93 Anisa 710 0 MET 99 1932 2583 1919 -367 -208 2 3 1 ATÓM 711 N CYS 100 -5,486 19.864 57.715 1,000 2 0.00 Anisa 711 N CYS 100 3178 2683 1739th -1753 -358 ATÓM 712 CA CYS 100 -4,645 20.181 56.554 1.000 16.64 Anisa 712 CA CYS 100 2213 2294 1817 - 924 - 563 4 6 8 ATÓM 713 CB CYS 100 -4,291 18.893 55.813 1.000 17.74 Anisa 713 CB CYS 100 2161 2174 2407 560 -766 1 0 5 3 ATÓM 714 SG CYS 100 -3,035 18.928 54.552 1,000 3 3.5 6 Anisa 714 SG CYS 100 5244 3511 3997 414 1508 6 0 1 ATÓM 715 C CYS 100 -5,347 21.121 55.590 1.000 13.48 Anisa 715 C CYS 100 1879 1415 1829 -68 240-9 1 ATÓM 716 0 CYS 100 -6,585 21.127 55.496 1.00014.49 Anisa 716 0 CYS 100 1880 1952 1673 -497 -57 ATÓM 717 N TYR 101 -4,589 21.921 54.1352 1.000 13. 3 5 Anisa 717 N TYR 101 1721 1677 1673 -254 -78 ATÓM 718 CA TYR 101 -5,016 22.753 53.755 1.000 10. 27 Anisa 718 CA TYR 101 927 1498 1477 -15 -141 - 2 3 1 ATÓM 719 CB TYR 101 -5,102 24.265 54124 1.000 13.60 Anisa 719 CB TYR 101 1626 1513 2027 -48 322-2 3 6 ATÓM 720 CG TYR 101 -5,498 25.025 52.863 1.000 17.3 1 Anisa 720 CG TYR 101 2373 1509 2694 -158 -103 1 9 4 ATÓM 721 CD1 TYR 101 -6,815 25.068 52.519 1.000 16. 3 8 Anisa 721 CD1 TYR 101 2464 752 3006 190 -227 5 ATÓM 722 CE1 TYR 101 -7,307 25715 51.412 1.000 17.0 1 Anisa 722 CE1 TYR 101 2755 715 2993 -86 -416 1 2 2 ATÓM 723 CD2 TYR 101 -4,616 25.679 52012 1.00019.51 Anisa 723 CD2 TYR 101 3032 1533 2847 -1144 -594 4 7 5 ATÓM 724 CE2 TYR 101 -5,065 26.321 50.872 1.000 20. 9 6 Anisa 724 CE2 TYR 101 2802 1949 3211 239 112 7 6 9 ATÓM 725 CZ TYR 101 -6,414 26.334 50.568 1.000 22.78 Anisa 725 CZ TYR 101 3238 2291 3126 - 1228 - 919 6 2 4 ATÓM 726 OH TYR 101 -6,875 26.986 49.442 1.000 23. 1 0 Anisa 726 OH TYR 101 3141 3112 2522 -14 -129 4 2 8 ATÓM 727 C TYR 101 -4,041 22.518 52.596 1.00011.25 Anisa 727 C TYR 101 1223 1398 1654 -323 103 2 2 2 ATÓM 728 0 TYR 101 -2,823 22.677 52787 1.000 12 .2 3 Anisa 728 0 TYR 101 1114 1750 1784 -87 130-2 0 ATÓM 729 N SER 102 -4,542 22.190 51405 1.000 11.17 Anisa 729 N SER 102 1355 1279 1611 -220 145-2 2 3 ATÓM 730 CA SER 102 -3,752 21802 50235 1,000 1 0.4 6 Anisa 730 CA SER 102 1144 1263 1568 61 -1 - 1 2 5. ATÓM 731 CB SER 102 -4,027 20343 49.908 1.00013.46 Anisa 731 CB SER 102 1668 1212 2234 325 105 - 3 0 1 ATÓM 732 OG SER 102 -3,723 19.487 51.025 1.00016.42 Anisa 732 OG SER 102 2291 1313 2637 -122 -43 9 7

SUBSTTTUIL · SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 114 -

ATÓM 733 C SER 102 - 4 .046 22668 49.008 1. 000 11.74 Anisa 733 C SER 102 1346 1500 1614 18 -39 --10 ATÓM 734 ABOUT SER 102 -5,148 23.148 48784 1,000 12.84 Anisa 734 ABOUT SER 102 1480 1410 1988 90 -66 2 4 9 ATÓM 735 N MET 103 -3,004 22.871 48.187 1,000 12:33 Anisa 735 N MET 103 1554 1722 1409 -262 -10 - 2 5 6 ATÓM 736 C A MET 103 -3,188 23603 46.938 1,000 12.92 Anisa 736 CA MET 103 1663 1681 1565 22 47 - 7 0 ATÓM 737 CB MET 103 -3,215 25.122 47. 179 1,000 17:51 Anisa 737 CB MET 103 2439 1634 2579 -363 811 - 4 4 ATÓM 733 CG MET 103 -1,929 25.808 47.549 1,000 2 0.07 Anisa 738 CG MET 103 2509 1470 3646 -538 688 376 ATÓM 739 SD MET 103 -2,136 27.614 47.689 1,000 18:10 Anisa 739 SD MET 103 2235 1665 2975 -3 -334 - 3 ATÓM 740 CE MET 103 -2,365 28.068 45.991 1,000 18:09 Anisa 740 CE MET 103 2319 1457 3098 -187 -718- 2 1 4 ATÓM 741 C MET 103 -2,152 23.221 45.892 1,000 12:57 Anisa 741 C MET 103 1420 1837 1519 119 -53 238 ATÓM 742 ABOUT MET 103 -1,120 22.573 46.175 1,000 12:57 Anisa 742 ABOUT MET 103 1094 1891 1792 -155 -165 276 ATÓM 743 N GLY 104 -2,418 23.650 44.655 1,000 12.83 Anisa 743 N GLY 104 1493 1958 1422 237 -124 - 3 4 ATÓM 744 CA GLY 104 -1,533 23.459 43.513 1,000 12.65 Anisa 744 CA GLY 104 1075 2188 1544 -93 -37 242 ATÓM 745 C GLY 104 -1,624 24.622 42.542 1,000 14:36 Anisa 745 C GLY 104 1909 1985 1561 -265 -294 142 ATÓM 746 ABOUT GLY 104 -2,033 25.700 42967 1,000 15.69 Anisa 746 ABOUT GLY 104 1628 2273 2060 163 -197 213 ATÓM 747 N THR 105 -1,242 24.397 41.276 1,000 14:52 Anisa 747 N THR 105 1829 2182 1504 -59 -375 319 ATÓM 748 CA THR 105 -1,218 25.452 40.279 1,000 15:27 Anisa 748 CA THR 105 1977 2223 1603 -105 -363 365 ATÓM 749 CB THR 105 -0,359 25.083 39.039 1,000 15.61 Anisa 749 CB THR 105 1936 2122 1873 -37 -106 554 ATÓM 750 OG1 THR 105 -0,884 23.876 38.446 1,000 16:16 Anisa 750 OG1 THR 105 1738 2260 2140 217 -285 151 ATÓM 751 CG2 THR 105 1,092 24.882 39.369 1,000 17:47 Anisa 751 CG2 THR 105 1918 2871 1847 -293 -227 527 ATÓM 752 C THR 105 -2,603 25.828 39.755 1,000 14.73 Anisa 752 C THR 105 1989 1694 1913 122 -340 199 ATÓM 753 ABOUT THR 105 -2,730 26.921 39174 1,000 19.91 Anisa 753 ABOUT THR 105 2579 2355 2632 23 -438 1 0 0 4 ATÓM 754 N ALA 106 -3,587 24.960 39913 1,000 16:57 Anisa 754 N ALA 106 1836 2413 2047 2 -260 661 ATÓM 755 CA ALA 106 -4,975 25167 39.465 1,000 14.94 Anisa 755 CA ALA 106 1975 1904 1798 105 -456 365 ATÓM 756 CB ALA 106 -5,054 24.945 37.965 1,000 17.75 Anisa 756 CB ALA 106 2006 2862 1876 140 -201 - 2 2 ATÓM 757 C ALA 106 -5,942 24.251 40.222 1,000 16:26 Anisa 757 C ALA 106 1710 2174 2293 327 -127 491 ATÓM 758 ABOUT ALA 106 -5,498 23.398 41.013 1,000 14:57 Anisa 758 ABOUT ALA 106 1622 1971 1945 213 -21 337 ATÓM 759 N ASP 107 -7,253 24.410 40.008 1,000 16.71 Anisa 759 N ASP 107 1768 2096 2485 540 -22 304 ATÓM 760 C A ASP 107 -8,310 23.638 40.633 1,000 16:10 Anisa 760 C A ASP 107 1696 2175 2246 51 -485 - 1 4 ATÓM 761 CB ASP 107 -8,231 22.171 40.211 1,000 9.17 Anisa 761 CB ASP 107 1299 2385 2808 144 -203-3 9 9 ATÓM 762 CG ASP 107 -8,418 21.966 38.720 1,000 1.54 Anisa 762 CG ASP 107 2385 2894 2906 84 -317-7 2 2 ATÓM 763 OD1 ASP 107 -9,452 22.445 38.189 1. 000 > 23.92

SUBS11 LUTE SHEET (RULE 26)

WO 99/33994

PCT'GB9S / 03860

- 115 -

Anisa 763 ODL ASP 1 0 7 3 4 4 1 2970 2672 O98 - ¾ 5 3 - 7 ¾ ATÓM 7 64 OD2 ASP 107 -7,563 21.311 38.080 1. 000 - * 4> 8 8 Anisa 764 OD2 ASP 107 2496 4004 2954 105 244-6 7 9 ATÓM 765 C ASP 107 -S .285 23.785 42.160 1. 000 14:16 Anisa 765 C ASP 107 1261 1918 2.2 01 237 -447 153 ATÓM 766 ABOUT ASP 107 -6,507 22.850 42.936 1,000 16.67 Anisa 766 ABOUT ASP 107 2017 1927 23 90 -189 -196 9 7 ATÓM 767 N ASN 108 -8,027 25.020 42.598 1,000 15:34 Anisa 767 N ASN 108 2093 1866 18 70 82 51 2 3 9 ATÓM 768 C A ASN 108 -7,967 25.314 44 .031 1,000 13.68 Anisa 768 CA ASN 108 1479 1823 1898 153 107 257 ATÓM 769 CB ASN 108 -6,925 26.420 44.272 1,000 15.60 Anisa 769 CB ASN 108 1593 2026 2309 16 267 - 9 8 ATÓM 770 CG ASN 108 -5,516 25942 43.963 1,000 15:23 Anisa 770 CG ASN 108 1505 2141 2142 5 -53 2 ATÓM 771 OD1 ASN 108 -5,086 24.932 44505 1,000 15:40 Anisa 771 OD1 ASN 108 1412 2442 1998 -5 -239 188 ATÓM 772 ND2 ASN 108 -4,823 26.678 43.094 1,000 16.96 Anisa 772 ND2 ASN 108 1593 2198 2652 339 393 222 ATÓM 773 C ASN 108 -9,310 25.708 44.642 1,000 14:55 Anisa 773 C ASN 108 1471 1937 2120 261 191 526 ATÓM 774 0 ASN 108 -10,222 26.170 43. 958 1,000 16.89 Anisa 774 0 ASN 108 1861 2336 2219 716 -109 1 4 ATÓM 775 N LEU 109 -9,412 25512 45.954 1,000 13:42 Anisa 775 N LEU 109 1458 1648 1994 179 130 9 ATÓM 776 CA LEU 109 -10,602 25.796 46.769 1,000 13:53 Anisa 776 CA LEU 109 1094 2122 1923 -52 - 86 - 2 5 6 ATÓM 777 CB LEU 109 -11,187 24.499 47.331 1,000 14:50 Anisa 777 CB LEU 109 1382 1959 2169 119 454 - 4 6 8 ATÓM 778 CG LEU 109 -11,580 23.383 46.370 1,000 15:21 Anisa 778 CG LEU 109 1593 1785 2403 235 62 - 3 4 2 ATÓM 779 CD1 LEU 109 -11,931 22.083 47.089 1,000 18:26 Anisa 779 CD1 LEU 109 2460 1674 2806 382 -414-9 4 ATÓM 780 CD2 LEU 109 -12,780 23.783 45529 1,000 2.36 Anisa 780 CD2 LEU 109 3055 2391 3052 44 -1155 288 ATÓM 781 C LEU 109 -10,203 26.794 47.840 1,000 13:54 Anisa 781 C LEU 109 1179 1989 1979 76 -116-2 2 9 ATÓM 782 0 LEU 109 -9,416 26428 48.717 1,000 16:15 Anisa 782 0 LEU 109 2196 2210 1730 -52 -366 3 2 ATÓM 783 N PHE 110 -10,706 28025 47.786 1,000 16:11 Anisa 783 N PHE 110 1369 2042 2 7 09 105 -118-2 8 8 ATÓM 784 CA PHE 110 -10,298 29.079 48.732 1,000 5.17 Anisa 784 CA PHE 110 1626 1801 3050 -116 259 - 3 7 2 ATÓM 785 CB PHE 110 -9,660 30.259 47.991 1,000 17.94 Anisa 785 CB PHE 110 1423 2366 3027 -290 229 - 1 2 9 ATÓM 786 CG PHE 110 -8,425 29.972 47165 1,000 20:32 Anisa 786 CG PHE 110 1702 2650 3 3 68 -176 458 - 3 8 5 ATÓM 787 CD1 PHE 110 -7,257 29598 47.793 1,000 2 0.35 Anisa 787 CD1 PHE 110 1885 2462 3387 461 574 - 7 0 7 ATÓM 788 CD2 PHE 110 -8,405 30.110 45.789 1,000 2 0.31 Anisa 788 CD2 PHE 110 2073 2226 3419 512 712 - 2 7 4 ATÓM 789 CE1 PHE 110 -6,102 29.347 47.065 1,000 19:49 Anisa 789 CE1 PHE 110 1958 2116 3332 176 748 - 6 3 1 ATÓM 790 CE2 PHE 110 -7,288 29.846 45.050 1,000 2 0.65 Anisa 790 CE2 PHE 110 2158 2094 3596 758 725 - 3 2 1 ATÓM 791 CZ PHE 110 -6,118 29.496 45.694 1,000 19:43 Anisa 791 CZ PHE 110 1925 2131 3327 219 542-7 8 0 ATÓM 792 C PHE 110 -11,495 29.556 49.538 1,000 i 17.08 Anisa 792 C PHE 110 1774 1806 2911 -74 4 14 - 1 2 1 ATÓM 793 0 PHE 110 -12,562 29.792 48 .929 1,000 1.26 Anisa 793 0 PHE 110 1849 2577 3650 405 1 77 - 4 4 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-116-

ATÓM 794 N PRO 111 -11,406 29.717 50.851 1. 000 19:41 Anisa 794 N PRO 111 2279 2110 2985 -386 «-314 ATÓM 795 CD PRO 111 -10,278 29.322 51.705 1,000 19:20 Anisa 795 CD PRO 111 2773 1880 2640 -'417 2 5 5 - 5 1 5 ATÓM 796 CA PRO 111 -12,549 30.252 51.604 1,000 2 1.47 Anisa 796 CA PRO 111 3026 1924 3206 -50 7 2 8 - 6 4 5 ATÓM 797 CB PRO 111 -12,167 30.007 53.055 1,000 2 3.63 Anisa 797 CB PRO 111 3789 2054 3137 334 776 - 5 7 4 ATÓM 798 CG PRO 111 -10,775 29.535 53.100 1,000 2 2.33 Anisa 798 CG PRO 111 2767 2908 2809 -1006 6 2 3 - 4 1 5 ATÓM 799 C PRO 111 -12,828 31739 51.433 1,000 2 3.88 Anisa 799 C PRO 111 3139 2049 3887 78 -142 - 4 7 9 ATÓM 800 ABOUT PRO 111 -13,919 32194 51.834 1,000 6.77 Anisa 800 0 PRO 111 3800 2818 3555 992 -91- 3 9 7 ATÓM 801 N SER 112 -11,906 32517 50.872 1,000 5.19 Anisa 801 N SER 112 3514 2269 3788 -247 -856 282 ATÓM 802 CA SER 112 -12,300 33.919 50.631 1,000 6.43 Anisa 802 CA SER 112 2654 2655 4734 496 1364 456 ATÓM 803 CB SER 112 -12,506 34.712 51912 1,000 3 3.37 Anisa 803 CB SER 112 3122 3663 5895 172 2582 - 5 0 0 ATÓM 804 OG SER 112 -11,322 34719 52688 1,000 6.94 Anisa 804 OG SER 112 6530 2154 5351 1399 206-4 4 5 ATÓM 805 C SER 112 -11,262 34.587 49.723 1,000 6.62 Anisa 805 C SER 112 2613 2546 4956 1021 1668 651 ATÓM 806 ABOUT SER 112 -10,219 34.029 49.414 1,000 2 2.81 Anisa 806 ABOUT SER 112 2241 2782 3645 800 836 - 4 0 0 ATÓM 807 N GLY 113 -11,570 35.802 49.279 1,000 8.93 Anisa 807 N GLY 113 2937 2947 5108 1008 1176 119 8 ATÓM 808 CA GLY 113 -10,659 36.478 48.365 1,000 3 0.79 Anisa 808 CA GLY 113 2992 3606 5102 381 799 1 4 0 0 ATÓM 809 C GLY 113 -9,362 36.829 49.070 1,000 3 1.83 Anisa 809 C GLY 113 3297 3919 4878 262 896 5 2 8 ATÓM 810 ABOUT GLY 113 -8,294 36.790 48459 1,000 25.85 Anisa 810 ABOUT GLY 113 2920 2317 4585 857 450 - 2 0 4 ATÓM 811 N ASP 114 -9,479 37145 50.365 1,000 29.56 Anisa 811 N ASP 114 3487 2877 4868 866 1104 760 ATÓM 812 CA ASP 114 -8,257 37.463 51.122 1,000 26.15 Anisa 812 CA ASP 114 3189 2680 4066 1028 1584 542 ATÓM 813 CB ASP 114 -8,628 37937 52.526 1,000 3 3.81 Anisa 813 CB ASP 114 5580 2697 4569 1774 1691 - 2 3 0 ATÓM 814 CG ASP 114 -7,904 39.232 52.840 1,000 4 0.77 Anisa 814 CG ASP 114 6798 3734 4960 719 694 - 2 4 8 ATÓM 815 OD1 ASP 114 -8,330 40.277 52.295 1,000 4 8.61 Anisa 815 OD1 ASP 114 6014 2534 9920 1703 931 -913 ATÓM 816 OD2 ASP 114 -6,932 39.178 53622 1,000 5 4.35 Anisa 816 OD2 ASP 114 5258 7609 7783 -868 496 1 6 0 2 ATÓM 817 C ASP 114 -7,310 36.281 51231 1,000 5.23 Anisa 817 C ASP 114 2621 2102 4033 444 1874 340 ATÓM 818 ABOUT ASP 114 -6,111 36.371 50.955 1,000 5.22 Anisa 818 ABOUT ASP 114 2423 2277 3677 131 1411 -461 ATÓM 819 N PHE 115 -7,854 35.160 51637 1,000 23:21 Anisa 819 N PHE 115 2945 1890 3984 -130 1292 - 2 2 8 ATÓM 820 CA PHE 115 -7,120 33.896 51.690 1,000 19.93 Anisa 820 CA PHE 115 2562 1908 3102 -198 655-2 9 4 ATÓM 821 CB PHE 115 -8,085 32.792 52157 1,000 19:49 Anisa 821 CB PHE 115 2378 1754 3275 64,881 - 3 1 4 ATÓM 822 CG PHE 115 -7,523 31.445 52540 1,000 17:25 Anisa 822 CG PHE 115 2053 1589 2912 -56 346 - 6 9 5 ATÓM 823 CD1 PHE 115 -7,637 30951 53833 1,000 19:00 Anisa 823 CD1 PHE 115 2728 1539 2950 73,496 - 6 8 3 ATÓM 824 CD2 PHE 115 -6,868 30.634 51 .615 1,000 17 8 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / G B98 / 03860

- 117-

Anisa 824 CD2 PHE 115 1933 1931 2927 7 298 - 8 0 0 ATÓM 825 CE1 PHE 115 -7,100 29.711 54.163 1.000-2-0 ». 2 5 Anisa 825 CE1 PHE 115 2825 1825 3042 317 341-5 5 7 5 ATÓM 826 CE2 PHE 115 -6,338 29.412 51.955 1,000 19:11 Anisa 826 CE2 PHE 115 1865 2158 3237 336 351-8 8 5 ATÓM 827 CZ PHE 115 -6,452 28936 53.233 1,000 19:39 Anisa 827 CZ PHE 115 2068 1910 3390 320 248-6 6 9 ATÓM 828 C PHE 115 -6,506 33624 50.327 1,000 17.66 Anisa 828 C PHE 115 1964 1945 2878 61 344 1 6 ATÓM 829 ABOUT PHE 115 -5,324 33.315 50.271 1,000 17:34 Anisa 829 ABOUT PHE 115 1868 2107 2513 -132 179 157 ATÓM 830 N GLU 116 -7,310 33.683 49.263 1,000 18:21 Anisa 830 N GLU 116 1921 1934 3065 547 281 6 2 ATÓM 831 CA GLU 116 -6,848 33.387 47.907 1,000 19.99 Anisa 831 CA GLU 116 2128 2618 2851 81 231 2 2 2 ATÓM 832 CB GLU 116 -7,968 33.605 46884 1,000 18.61 Anisa 832 CB GLU 116 2058 1952 3060 231 244 270 ATÓM 833 CG GLU 116 -7,398 33.378 45.482 1,000 18.61 Anisa 833 CG GLU 116 1813 2288 2S71 295 -32 - 3 3 ATÓM 834 CD GLU 116 -8,442 33.230 44.412 1,000 22:40 Anisa 834 CD GLU 116 1908 3193 3410 -122 -278-9 1 ATÓM 835 OE1 GLU 116 -9,654 33.272 44.678 1,000 3 0.82 Anisa 835 OE1 GLU 116 1793 4465 5452 273 -414 - 2 3 ATÓM 836 OE2 GLU 116 -8,085 33063 43.225 1,000 30.24 Anisa 836 OE2 GLU 116 3333 5132 3026 382 -657 3 2 7 ATÓM 837 C GLU 116 -5,620 34.211 47.535 1,000 18.82 Anisa 837 C GLU 116 2090 2069 2990 294 120 4 8 7 ATÓM 838 ABOUT GLU 116 -4,605 33.701 47.049 1,000 17:41 Anisa 838 ABOUT GLU 116 2228 1780 2606 45 25S 2 8 2 ATÓM 839 N ARG 117 -5,660 35.508 47.777 1,000 2.21 Anisa 839 N ARG 117 2313 2185 3437 408 220 9 0 ATÓM 840 CA ARG 117 -4,560 36.420 47.431 1,000 2 1.35 Anisa 840 CA ARG 117 2337 1800 3976 466 147-3 3 1 ATÓM 841 C ARG 117 -3,291 36054 48.192 1,000 2 0.52 Anisa 841 C ARG 117 2292 2124 3 3 BO 353 288-10 ATÓM 842 ABOUT ARG 117 -2,186 35.969 47.636 1,000 18.96 Anisa 842 ABOUT ARG 117 2223 1664 3316 138 320 2 3 1 ATÓM 843 CB ARG 117 -4,971 37.885 47.693 1,000 25.59 Anisa 843 CB ARG 117 3237 1900 4587 929 1881 6 3 2 ATÓM 844 CG ARG 117 -3,881 38908 47.478 1,000 32.57 Anisa 844 CG ARG 117 5212 1925 5237 -281 1082 6 2 3 ATÓM 845 CD ARG 117 -4,325 40323 47.859 1,000 6.56 Anisa 845 CD ARG 117 6009 2157 5724 149 1773 6 6 3 ATÓM 846 NE ARG 117 -5,162 40.335 49.056 1,000 44.43 Anisa 846 NE ARG 117 7200 3742 5940 -96 2344 - 15 ATÓM 847 CZ ARG 117 -4,763 40.501 50306 1,000 5.48 Anisa 847 CZ ARG 117 6422 4804 6054 -370 2388 - 2 7 3 ATÓM 848 NH1 ARG 117 -3,484 40.683 50.619 1,000 5 3.21 Anisa 848 NH1 ARG 117 6867 6451 6900 -2,543 2487 354 ATÓM 849 NH2 ARG 117 -5,647 40487 51301 1,000 50.00 Anisa 849 NH2 ARG 117 6265 6511 6220 224 2433 -1534 ATÓM 850 N ILE 118 -3,439 35.832 49.493 1,000 19:30 Anisa 850 N ILE 118 2275 1838 3221 128 407 - 6 3 4 ATÓM 851 CA ILE 118 -2,275 35.527 50.331 1,000 18:25 Anisa 851 CA ILE 118 2376 1745 2811 78,530 - 4 4 9 ATÓM 852 CB ILE 118 -2,665 35.597 51.1320 1,000 18:24 Anisa 852 CB ILE 118 2201 1726 3003 346 906 - 3 0 7 ATÓM 853 CG2 ILE 118 -1,712 34.851 52.732 1,000 l 18.49 Anisa 853 CG2 ILE 118 2077 2158 2792 -202 308 - 5 4 0 ATÓM 8S4 CG1 ILE 118 -2,877 37031 52.368 1,000 l24.69 Anisa 854 CG1 ILE 118 4436 1808 3136 284 1382 - 4

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 118-

ATÓM 855 CD1 ILE 118 -3,786 37.025 53.582 1,000 29.63 Anisa 855 CDi ILE 118 6169 3096 1994 189 058 - 1 0 7 8 ATÓM 856 C ILE 118 -1,692 34.172 49.959 1,000 15.65 Anisa 856 C ILE 118 2316 1549 2082 -89 573-1 1 7 ATÓM 857 ABOUT ILE 118 -0,463 34.035 49.802 1,000 14:59 Anisa 857 ABOUT ILE 118 2240 1255 2051 16 286 i 214 ATÓM 858 N TRP 119 -2,523 33.139 49.784 1,000 14:44 Anisa 858 N TRP 119 2125 1592 1771 47 128 1-71 ATÓM 859 CA TRP 119 -2,010 31.795 49.518 1,000 13.68 Anisa 859 C A TRP 119 1712 1529 1957 -61 220 4 0 ATÓM 860 CB TRP 119 -3,089 30.755 49.932 1,000 14.93 Anisa 860 CB TRP 119 1819 1729 2123 -234 295 - 3 6 ATÓM 861 CG TRP 119 -2,864 30.482 51.420 1,000 16:19 Anisa 861 CG TRP 119 1640 2364 2146 -168 582 167 ATÓM 862 CD2 TRP 119 -2,116 29.430 51.993 1,000 2 0.41 Anisa 862 CD2 TRP 119 3189 2414 2151 202 523 405 ATÓM 863 CE2 TRP 119 -2,177 29.580 53.392 1,000 19.84 Anisa 863 CE2 TRP 119 3536 1818 2184 -439 234 137 ATÓM 864 CE3 TRP 119 -1,390 28357 51.456 1,000 23.94 Anisa 864 CE3 TRP 119 5382 1647 2068 561 126 400 ATÓM 865 CDI TRP 119 -3,340 31.223 52.460 1,000 5.20 Anisa 865 CDI TRP 119 3207 2343 2069 -9 189 -13 9 ATÓM 866 NE1 TRP 119 -2,938 30.689 53649 1,000 2 0.32 Anisa 866 NE1 TRP 119 2806 2726 2188 -96 -68 - 1 8 ATÓM 867 CZ2 TRP 119 -1,547 28.714 54.281 1,000 22:12 Anisa 867 CZ2 TRP 119 4071 2256 2078 -17 105 2 2 ATÓM 868 GB3 TRP 119 -0,761 27.490 52.332 1,000 21:52 Anisa 868 GB3 TRP 119 4214 2168 1794 311 -194 19 7 ATÓM 869 CH2 TRP 119 -0,847 27674 53.715 1,000 24.34 Anisa 869 CH2 TRP 119 5349 2047 1850 329 148 18 3 ATÓM 870 C TRP 119 -1,521 31.634 48.095 1,000 14:27 Anisa 870 C TRP 119 2180 1259 1985 -187 334-6 6 ATÓM 871 ABOUT TRP 119 -0,569 30.865 47.855 1,000 14.73 Anisa 871 ABOUT TRP 119 1996 1653 1946 -67 362 1 0 1 ATÓM 872 N THR 120 -2,109 32.325 47.116 1,000 13.99 Anisa 872 N THR 120 2231 1237 1848 106 628 - 1 3 7 ATÓM 873 CA THR 120 -1,541 32.275 45.762 1,000 15:19 Anisa 873 CA THR 120 1903 2093 1774 9 43S i - 2 4 2 ATÓM 874 CB THR 120 -2,492 32.983 44.787 1,000 16:41 Anisa 874 CB THR 120 1934 2304 1995 -331 152 6 6 ATÓM 875 OG1 THR 120 -3,738 32.297 44.766 1,000 18:53 Anisa 875 OG1 THR 120 1891 2288 2863 -236 195 4 0 6 ATÓM 876 CG2 THR 120 -1,974 32.906 43.358 1,000 2.18 Anisa 876 CG2 THR 120 2135 2602 2108 324 321 3 1 8 ATÓM 877 C THR 120 -0,145 32.870 45.727 1,000 14:19 Anisa 877 C THR 120 1868 2050 1475 87 285-1 ATÓM 878 ABOUT THR 120 0756 32.299 45078 1,000 13.62 Anisa 878 ABOUT THR 120 1864 1692 1620 301 354 217 ATÓM 879 N GLN 121 0114 33962 46.429 1,000 14:55 Anisa 879 N GLN 121 1721 1672 2136 304 175-6 7 ATÓM 880 CA GLN 121 1,459 34.548 46.483 1,000 15.80 Anisa 880 CA GLN 121 2067 1666 2271 -18 -119 362 ATÓM 881 C GLN 121 2,465 33.642 47176 1,000 13.73 Anisa 881 C GLN 121 1747 1665 1806 -30 18 1 1 4 ATÓM 882 ABOUT GLN 121 3603 33452 46.685 1,000 15:36 Anisa 882 ABOUT GLN 121 2063 1688 2084 48 360-4 4 ATÓM 883 CB GLN 121 1,315 35.918 47.154 1,000 18.85 Anisa 883 CB GLN 121 2537 1,426 3200 -73 -5 3 5 7 ATÓM 884 CG GLN 121 2,639 36.558 47.543 1,000 18.88 Anisa 884 CG GLN 121 2507 1788 2878 59 9 - 2 4 7 ATÓM 885 CD GLN 121 3.468 36.936 46.337 1,000 2 0.70

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

Anisa 885 CD GLN 121 2584 ATÓM 886 ΟΞ1 GLN 121 2935 Anisa 886 OE1 GLN 121 2695 ATÓM 887 NE2 GLN 121 4779 Anisa 887 NE2 GLN 121 2426 ATÓM 888 N TYR 122 2.081 Anisa 888 N TYR 122 1747 ATÓM 889 C A TYR 122 2. 896 Anisa 889 C A TYR 122 1901 ATÓM 890 CB TYR 122 2.211 Anisa 890 CB TYR 122 2045 ATÓM 891 CG TYR 122 2.994 Anisa 891 CG TYR 122 1966 ATÓM 892 CD1 TYR 122 4271 Anisa 892 CD1 TYR 122 1788 ATÓM 893 CE1 TYR 122 5003 Anisa 893 CE1 TYR 122 2131 ATÓM 894 CD2 TYR 122 2,445 Anisa 894 CD2 TYR 122 3308 ATÓM 895 CE2 TYR 122 3,140 Anisa 895 CE2 TYR 122 3772 ATÓM 896 CZ TYR 122 4413 Anisa 896 CZ TYR 122 2985 ATÓM 897 OH TYR 122 5068 Anisa 897 OH TYR 122 4830 ATÓM 898 C TYR 122 3.218 Anisa 898 C TYR 122 1833 ATÓM 899 0 TYR 122 4395 Anisa 899 0 TYR 122 1896 ATÓM 900 N PHE 123 2,224 Anisa 900 N PHE 123 1950 ATÓM 901 CA PHE 123 2.482 Anisa 901 CA PHE 123 1731 ATÓM 902 CB PHE 123 1.139 Anisa 902 CB PHE 123 2048 ATÓM 903 CG PHE 123 1.311 Anisa 903 CG PHE 123 2173 ATÓM 904 CD1 PHE 123 1.281 Anisa 904 CD1 PHE 123 1857 ATÓM 905 CD2 PHE 123 1.511 Anisa 905 CD2 PHE 123 1450 ATÓM 906 CE1 PHE 123 1,468 Anisa 906 CE1 PHE 123 2282 ATÓM 907 CE2 PHE 123 1.715 Anisa 907 CE2 PHE 123 2098 ATÓM 908 CZ PHE 123 1.706 Anisa 908 CZ PHE 123 1442 ATÓM 909 C PHE 123 3489 Anisa 909 C PHE 123 2004 ATÓM 910 0 PHE 123 4424 Anisa 910 0 PHE 123 1591 ATÓM 911 N ASP 124 3.294 Anisa 911 N ASP 124 1490 ATÓM 912 CA ASP 124 4207 Anisa 912 CA ASP 124 1505 ATÓM 913 CB ASP 124 3.708 Anisa 913 CB ASP 124 2650 ATÓM 914 CG ASP 124 4.470 Anisa 914 CG ASP 124 5327 ATÓM 915 OD1 ASP 124 4541 Anisa 915 OD1 ASP 124 6362

-119-

2138 3.L4 2 -373 -J 5 2 3 1 37.088 45224 1,000 · 4 7 2822 3019 -245 0 12 1 37.101 46.522 í. 000 5.22 3344 3611 127 -132 13 8 5 33.054 4E. 299 1,000 12:26 1514 1399 99 -55 > -258 32102 49.050 1,000 13:18 1643 1464 -20 -253 - 1 5 0 31724 50364 1,000 13.78 1435 1756 116 48-28 30.808 51.282 1,000 14:22 1681 1758 101 68 1 0 1 31.120 51722 1,000 17:48 1972 28 32 149 -5 4 2 0 30.284 52.576 1,000 18:55 2050 2868 102 -404 251 29.619 51731 1,000 2 0.72 1366 3197 -519 -1524 323 28.773 52.574 1,000 2 5.40 1812 4067 -782 -2084 873 29.101 52.992 1,000 2 0.93 1742 32 2 4 -96 -1145 313 28.230 53826 1,000 2 9.87 1998 4522 -680 -3078 621 30.876 48.209 1,000 12:33 1412 1439 89 -218 8 8 30.507 48.117 1,000 14:25 1861 1656 339 -242 216 30.269 47.573 1,000 11:28 1297 1041 6 -151 185 29.151 46.665 1,000 8.12 1219 1640 64 -60 l 2 6 28719 46.024 1,000 13.86 1550 1666 -104 -276 - 8 2 27.516 45,099 1,000 14:44 1677 163 7 142 -475-9 4 26.234 45.614 1,000 13.64 1563 1764 -42 -702 - 2 27664 43.729 1,000 13.81 2164 1634 -420 -295 - 2 5 8 25.141 44795 1,000 17:16 1819 2418 130 -855-6 6 4 4 26.559 42916 1,000 18:31 2657 2201 -1053 172-8 4 5 25.295 43445 1,000 16.71 2382 2 52 6 -36 -306 - 1,077 29.511 45.581 1,000 13:48 1472 1645 236 157 1 8 28.768 45.242 1,000 7.13 1498 1876 42 - 78 - 1 7 2 30.684 44.948 1,000 13.83 1575 2189 51,207,288 31036 43861 1,000 13.75 1330 2389 458 398 344 32.352 43242 1,000 18.95 1970 2580 656 -63 926 32708 41.989 1,000 7.54 2099 3036 -123 939 880 31.904 41.023 1,000 3 7.04 3225 4485 108 261 6 - 3 4 1

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S / 03860

- 120 -

ATÓM 916 OD2 ASP 1 2 4 4.9 7 S 33.843 42.011 1,000 3 2.60 Anisa 916 OD2 ASP 124 4724 3509 4151 -1539 8 5 1 ATÓM 917 C ASP 124 5645 31164 44.328 1,000 14:49 Anisa 917 C ASP 124 1493 1721 2293 327 485 4 8 2 ATÓM 918 0 ASP 124 6.591 30.721 43.674 1,000 14:52 Anisa 918 0 ASP 124 1477 1363 2679 289 497 3 0 7 ATÓM 919 N ARG 125 5866 31.777 45.499 1,000 3.14 Anisa 919 N ARG 125 1501 1271 2558 353 398 4 1 4 ATÓM 920 C A ARG 125 7214 31863 46.044 1,000 16:40 Anisa 920 C A ARG 125 1642 1625 2963 194 178 2 2 6 ATÓM 921 C ARG 125 7828 30494 46.346 1,000 14.69 Anisa 921 C ARG 125 1396 1688 2496 232 -25 1 5 3 ATÓM 922 0 ARG 125 8.999 30.245 46.034 1,000 14:10 Anisa 922 0 ARG 125 1279 1656 2424 7 -205 - 2 0 0 ATÓM 923 CB ARG 125 7213 32.705 47.318 1,000 18:13 Anisa 923 CB ARG 125 1950 1902 3035 787 -81 4 6 ATÓM 924 CG ARG 125 7045 34.193 47.041 1,000 2 3.51 Anisa 924 CG ARG 125 2232 1780 4919 883 -36 - 2 2 5 ATÓM 925 CD ARG 125 8.391 34.815 46.694 1,000 9.33 Anisa 925 CD ARG 125 3596 2824 4724 -667 237 - 18 7 ATÓM 926 NE ARG 125 8.194 36.262 46.803 1,000 3 2.99 Anisa 926 NE ARG 125 4350 2766 5418 -678 -1,642 15 6 ATÓM 927 CZ ARG 125 8868 37.153 47.495 1,000 7.38 Anisa 927 CZ ARG 125 2292 2758 5353 -276 -580 - 2 4 6 ATÓM 928 NH1 ARG 125 9.916 36821 48.235 1,000 8.55 Anisa 928 NH1 ARG 125 4611 3604 6433 449 -2,476 -669 ATÓM 929 NH2 ARG 125 8.491 38.423 47.442 1,000 3 0.26 Anisa 929 NH2 ARG 125 4062 2570 4865 -369 -835 3 6 3 ATÓM 930 N GLN 126 7.065 29.573 46.920 1,000 12:36 Anisa 930 N GLN 126 1316 1376 2002 248 -63 - 2 6 4 ATÓM 931 CA GLN 126 7524 28.201 47.153 1,000 13:39 Anisa 931 CA GLN 126 1765 1323 1999 219 -355 - 3 7 7 ATÓM 932 CB GLn 126 6.363 27.455 47.828 0.500 16:24 Anisa 932 CB GLn 126 2422 1391 2357 188 202 - 19 2 ATÓM 933 CG GLn 126 6.149 27.758 49.284 0.500 18.83 Anisa 933 CG GLn 126 2761 2021 2371 68 233 1-210 ATÓM 934 CD GLn 126 7077 27.146 50.298 0.500 2 3.94 Anisa 934 CD GLn 126 3578 2745 2774 -604 -757 3 3 ATÓM 935 OE1 GLn 126 7181 27.683 51.419 0.500 3 5.94 Anisa 935 OE1 GLn 126 6788 3731 3136 -578 -1,567 -478 ATÓM 936 NE2 GLn 126 7.774 26.055 50.008 0.500 2 4.63 Anisa 936 NE2 GLn 126 4491 1118 3751 -881 -2,407 4 6 2 ATÓM 937 CB BGLN 126 6.525 27.417 48.018 0.500 13:36 Anisa 937 CB BGLN 126 1695 1137 2245 602 -114 - 2 5 5 ATÓM 938 CG BGLN 126 6.604 27.750 49.497 0.500 18:28 Anisa 938 CG BGLN 126 2537 2257 2153 -68 -176 - 10 5 ATÓM 939 CD BGLN 126 5,442 27237 50.319 0.500 18:42 Anisa 939 CD BGLN 126 2227 2573 2198 344 -159 1 0 6 ATÓM 940 OE1 BGLN 126 5.605 26.442 51.242 0.500 5.36 Anisa 940 OE1 BGLN 126 3289 3517 2828 -100 -223 9 5 3 ATÓM 941 NE2 BGLN 126 4.231 27685 50.003 0.500 2 5.02 Anisa 941 NE2 BGLN 126 2427 2669 4413 1004 -83 - 2 9 8 ATÓM 942 C GLN 126 7.860 27.448 45.861 1,000 12.95 Anisa 942 C GLN 126 1506 1434 1979 307 -372 - 3 6 6 ATÓM 943 0 GLN 126 8.859 26.721 45.748 1,000 11.66 Anisa 943 0 GLN 126 1461 1142 1827 182 -85 1 5 9 ATÓM 944 N TYR 127 6.960 27.578 44868 1,000 11.61 Anisa 944 N TYR 127 1400 1276 1735 146 -168 - 1 0 ATÓM 945 CA TYR 127 7.152 26869 43.585 1,000 11:21 Anisa 945 CA TYR 127 1469 1242 1550 -92 -40 1 9 2 ATÓM 946 CB TYR 127 5. 901 26.940 42. 724 1,000 11.82

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98'03860

- 121 -

ANISOU 946 CB TYR 127 1346 1655 14 91 -13 82 4 7 ATÓM 947 CG TYR 127 5.791 2b. 069 43 .496 1,000 UL Anisa 947 CG TYR 127 1278 1428 1660 -4 -4 1 0 ATÓM 94S CD1 TYR 127 6.550 24.928 41 .270 1-. 000 11:28 Anisa 948 CD1 TYR 127 1030 1334 1521 -87 -100 3 3 ATÓM 949 CE1 TYR 127 6.406 24.153 4C.115 1,000 11:47 Anisa 949 CE1 TYR 127 1164 1167 2027 -51 -53 2 1 ATÓM 950 CD2 TYR 127 4871 26.410 40.500 1,000 11.98 Anisa 950 CD2 TYR 127 1677 1093 1784 204 -219 -10 0 ATÓM 951 THROUGH TYR 127 4,715 25.655 39357 1,000 11:37 Anisa 951 CE2 TYR 127 1539 1118 1665 140 -68 - 7 3 ATÓM 952 CZ TYR 127 5494 24.508 39.163 1,000 2.11 Anisa 952 CZ TYR 127 1202 1226 1750 91 48 -12 5 ATÓM 953 OH TYR 127 5.379 23.720 38.030 1,000 11:57 Anisa 953 OH TYR 127 1547 1138 17:12 94 177 - 3 4 ATÓM 954 C TYR 127 8386 27.392 42. 882 1,000 10.83 Anisa 954 C TYR 127 1296 989 1830 230 -43 3 7 8 ATÓM 955 ABOUT TYR 127 9.185 26.605 42.375 1,000 10.86 Anisa 955 ABOUT TYR 127 1292 1232 1603 164 -237 - 4 2 ATÓM 956 N THR 128 8.565 28716 42.865 1,000 10.98 Anisa 956 N THR 128 1554 976 1642 212 -9 5 5 7 ATÓM 957 C A THR 128 9766 29.305 42.295 1,000 11.80 Anisa 957 C A THR 128 1686 1125 1673 -47 -168 3 8 6 ATÓM 958 CB THR 128 9.605 30.849 42378 1,000 12.66 Anisa 958 CB THR 128 1873 1074 1864 -52 -233 5 2 1 ATÓM 959 OG1 THR 128 8.530 31.286 41.517 1,000 16.74 Anisa 959 OG1 THR 128 2223 1597 2542 124 -458 9 9 8 ATÓM 960 CG2 THR 128 10.878 31.510 41.893 1,000 16:54 Anisa 960 CG2 THR 128 1871 +420 778 3635 262 ! 655 13 8 ATÓM 961 C THR 128 11.040 .28.828 42.964 1,000 11:26 Anisa 961 C THR 128 1562 980 1738 -71 -162 148 ATÓM 962 ABOUT THR 128 11.995 28.458 42258 1,000 12:16 Anisa 962 ABOUT THR 128 1769 1092 175.3 17 26 2 7 9 ATÓM 963 N ALA 129 11.083 28.802 44.300 1,000 10:39 Anisa 963 N ALA 129 1183 1001 1763 70 -118 147 ATÓM 964 CA ALA 129 12.273 28.386 45037 1,000 10:59 Anisa 964 CA ALA 129 1206 944 1873 -69 -170 2 8 1 ATÓM 965 CB ALA 129 12.113 28.603 46.536 1,000 12:46 Anisa 965 CB ALA 129 2113 851 1769 -218 5 7 7 ATÓM 966 C ALA 129 12.575 26.906 44802 1,000 11:35 Anisa 966 C ALA 129 1258 882 2170 -16 -141 4 1 0 ATÓM 967 ABOUT ALA 129 13.738 26.485 44.641 1,000 10.93 Anisa 967 ABOUT ALA 129 1202 1157 1796 -36 -213 12 1 ATÓM 968 N SER 130 11.519 26.086 44.750 1,000 12:27 Anisa 968 N SER 130 1280 984 2398 -65 -1 - 2 4 ATÓM 969 CA SER 130 11.682 24.650 44.512 1,000 10.89 Anisa 969 CA SER 130 1623 876 1638 -85 3 7 0 ATÓM 970 CB ASER 130 10.342 23.940 44716 0.500 8.10 Anisa 970 CB ASER 130 1432 +420 603 1793 213 247 4 1 3 ATÓM 971 OG ASER 130 9.771 24.063 46.006 0.500 9.12 Anisa 971 OG ASER 130 1021 651 1792 91 1 - 1 2 3 ATÓM 972 CB BseRI 130 10.364 23.919 44.765 0.500 10.60 Anisa 972 CB BseRI 130 1687 822 1521 -45 318 1 5 8 ATÓM 973 OG BseRI 130 9.418 24098 43734 0.500 16:22 Anisa 973 OG BseRI 130 1717 1289 3156 137 -525 3 4 . 8 ATÓM 974 C SER 130 12.214 24.373 43.1L0 1,000 10:53 Anisa 974 C SER 130 1586 733 1684 -166 210 4 8 4 ATÓM 975 ABOUT SER 130 13.137 23.532 42.942 1,000 H1.17 Anisa 975 ABOUT SER 130 1385 1012 1849 -151 -95 1 4 1 0 ATÓM 976 N ARG 131 11.680 25.044 42.079 1,000 l 10.46 Anisa 976 N ARG 131 1578 861 1534 -87 -66 9 9

SUBSTTTUTE SHEET (RULE 26)

U Ο 99/33994

PCT / GB98 / 03860

ATÓM 977 CA Anisa 977 C A ATÓM 978 CB Anisa 978 CB ATÓM 979 CG Anisa 979 CG ATÓM 980 CD Anisa 980 CD ATÓM 981 NE Anisa 981 NE ATÓM 982 CZ Anisa 982 CZ ATÓM 983 NH1 Anisa 983 NH1 ATÓM 984 NH2 Anisa 984 NH2 ATÓM 985 C Anisa 985 C ATÓM 986 ABOUT Anisa 986 0 ATÓM 987 N Anisa 987 N ATÓM 988 CA Anisa 988 CA ATÓM 989 CB Anisa 989 CB ATÓM 990 C Anisa 990 C ATÓM 991 ABOUT Anisa 991 ABOUT ATÓM 992 N Anisa 992 N ATÓM 993 CA Anisa 993 CA ATÓM 994 CB Anisa 994 CB ATÓM 995 CG1 Anisa 995 CG1 ATÓM 996 CG2 Anisa 996 CG2 ATÓM 997 C Anisa 997 C ATÓM 998 ABOUT Anisa 998 ABOUT ATÓM 999 N Anisa 999 N ATÓM 1000 CA Anisa 1000 CA ATÓM 1001 CB Anisa 1001 CB ATÓM 1002 C Anisa 1002 C ATÓM 1003 0 Anisa 1003 ABOUT ATÓM 1004 N Anisa 1004 N ATÓM 1005 CA Anisa 1005 CA ATÓM 1006 CB Anisa 1006 CB ATÓM 1007 CG

ARG 131 12.260 ARG 131 1480 ARG 131 11.426 ARG 131 1893 ARG 131 10.003 ARG 131 1707 ARG 131 9.349 ARG 131 2078 ARG 1319.453 ARG 131 2,716 ARG 131 8.629 ARG 131 3688 ARG 131 7.631 ARG 131 2792 ARG 131 8.771 ARG 131 4 64 9 ARG 131 13.714 ARG 131 1542 ARG 131 14.568 ARG 131 1544 ALA 132 14.028 ALA 132 1477 ALA 132 15.379 ALA 132 1539 ALA 132 15.429 ALA 132 1711 ALA 132 16.393 ALA 132 1085 ALA 132 17.481 ALA 132 1081 VAL 133 16.061 VAL 133 1260 VAL 133 17.011 VAL 133 1505 VAL 133 16.738 VAL 133 1376 VAL 133 15.550 VAL 133 1705 VAL 133 17.981 VAL 133 1755 VAL 133 17.079 VAL 133 1376 VAL 133 18.198 VAL 133 1391 ALA 134 15.982 ALA 134 1399 ALA 134 16.084 ALA 134 1106 ALA 134 14.699 ALA 134 1254 ALA 134 16.968 ALA 134 1393 ALA 134 17.712 ALA 134 1254 ARG 135 16.908 ARG 135 1517 ARG 135 17.773 ARG 135 1854 ARG 135 17.393 ARG 135 2203 ARG 135 17.753

122 -

24. 839 40.742 1110 1438 25.553 39.679 1369 1673 25.065 39.431 1735 1742 25.669 38206 1973 2677 27.113 38.015 2034 2757 28.004 38.568 1878 2503 27.634 39366 3142 2166 29.310 38.361 1822 4103 25.323 40.688 1078 1339 24.683 40.080 1105 1506 26.438 41.343 1129 1563 26983 41.343 945 1735 9 28.344 42.048 1171 1987 26.045 41.995 1107 2197 25.832 41432 1809 1599 25.490 43.175 1356 1623 24.587 43.840 1529 1380 24.418 45344 1674 1564 23.501 45.608 2316 1662 23.864 46.033 2340 1845 23.268 43.065 1363 1711 22.733 42925 1453 1545 22.758 42.480 1517 1973 21.557 41621 1220 1691 21.096 41.186 1589 1794 21.797 40399 1399 1987 20.924 39.970 1358 1574 22.995 39.809 1230 1824 23.353 38.676 1158 2015 24.734 38.170 1339 1994 25.160 36.797

1,000 1 0.6 0 61 -2 8 & J-8 2 1,000 12,99 6'3 -5 25 2 7 6

1.000 1 3.6 4 335 -559 - 8 6

1,000 17.71 81 -983 7 0 1

1,000 1 9.7 6 -25 -525,713

1,000 21,24 -8 -128,647

1,000 2 1.3 2 -486 -667 5 7

1,000 2 7.8 3 -90 -422 5 6 1

1.000 1 0.4 2 50 -1031

1,000 1 0.9 4,177 -134 4 2

1,000 10,97 74 -364- 4 5

1.000 1 1.1 0 -1029 7

1,000 12.82 -48 -248 - 1 9 8

1,000 11,55 -197 3057 4 5

1,000 11.81 -20417 -9

1,000 11.16 -148 51 3 5 0

1,000 11.62 -69 -297 8 9

1,000 12.14 -74 -25 3 6 4

1.00014.96 -707 8 - 3 5 7

1,000 15.63 -341 -677 5 5 1

1,000 1 1.7 1 -24 -425 1 6 9

1,000 11,55 -4 -116,398

1,000 12.87 28 -334 - 2 2 8

1,000 10.57 153 -298 9 6

1,000 12.2 0 35 -303 - 1 2 7

1,000 12.58 272 -4 2 7 7

1,000 1,000 1.01 83 -268 2 6

1,000 12.03 -62 -327 8 7

1,000 13,23 -270 -209 1 6 1

1,000 1 4.5 7 -45 -541 222

1.000 1 9.2 2

SUBSII sorry SHEET (RULE 26) \ VO 99/33994

PCT / GB98 / 03860

- 123 - Anisa 1007 CG ARG 135 4 204 1120 19 8 0 -490 -433 1 5 1 ATÓM 1008 CD ARG 135 17.237 26.563 36.471 1. 000 VZ. 1 4 Anisa 1008 CD ARG 135 404 6 1500 26 68 -159 315 822 ATÓM 1009 NE ARG 135 15.631 26.607 36.077 1. 000 2 2.66 Anisa 1009 NE ARG 135 4239 1404 2965 -94 48 2 5 7 ATÓM 1010 CZ ARG 135 14.802 27.184 36.684 1,000 2 1.69 Anisa 1010 CZ ARG 135 4004 1906 2333 -506 6 4 ATÓM 1011 NNL ARG 135 14.917 27.843 37.833 1,000 2.26 Anisa 1011 NH1 ARG 135 4114 2532 1812 460 -833 341 ATÓM 1012 NH2 ARG 135 13 .582 27.113 36.149 1,000 2.31 Anisa 1012 NH2 ARG 135 4000 2243 2234 -544 -419 8 ATÓM 1013 C ARG 135 19.251 23.275 39057 1,000 12.70 Anisa 1013 C ARG 135 1742 1264 1821 -119 -16 430 ATÓM 1014 ABOUT ARG 135 20.069 22818 38238 1,000 14.67 Anisa 1014 ABOUT ARG 135 2133 1529 19 LO 19 169 3 9 1 ATÓM 1015 N GLU 136 19.572 23.712 40.266 1,000 12:15 Anisa 1015 N GLU 136 1423 1372 1820 -36 71 4 3 0 ATÓM 1016 C A GLU 136 20.960 23.630 40 763 1,000 14:52 Anisa 1016 CA GLU 136 1622 1701 2194 -90 -197 371 ATÓM 1017 CB GLU 136 21.212 24.513 41.981 1,000 15:59 Anisa 1017 CB GLU 136 1502 1781 2642 14 -232 1 1 ATÓM 1018 CG GLU 136 21.064 26.020 41.783 1,000 1.18 Anisa 1018 CG GLU 136 2010 1762 307 1 -232 -153 126 ATÓM 1019 CD GLU 136 21798 26.484 40.537 1,000 2 0.18 Anisa 1019 CD GLU 136 2071 2079 3519 -308 88 3 6 9 ATÓM 1020 OEL GLU 136 22.987 26.148 40.394 1,000 2 4.64 Anisa 1020 OEL GLU 136 2060 2937 4364 -262 338 615 ATÓM 1021 OE2 GLU 136 21.195 27.150 39.670 1,000 24.19 Anisa 1021 OE2 GLU 136 2479 2327 4385 -381 316 14 2 6 ATÓM 1022 C GLU 136 21.364 22.186 41.076 1,000 14:00 Anisa 1022 C GLU 136 1338 1619 2361 -112 -442 223 ATÓM 1023 ABOUT GLU 136 22.508 21.781 40.833 1,000 13.86 Anisa 1023 ABOUT GLU 136 1366 1890 2009 -100 -287 329 ATÓM 1024 N VAL 137 20472 21.338 41.580 1,000 11.78 Anisa 1024 N VAL 137 1309 1451 1715 148 -226 8 5 ATÓM 1025 CA VAL 137 20.753 19.896 41.771 1,000 12:49 Anisa 1025 CA VAL 137 1369 1522 185.3 240 -69 289 ATÓM 1026 CB VAL 137 19.560 19.165 42.429 1,000 12:41 Anisa 1026 CB VAL 137 1422 1424 1869 -67 - 85 - 2 0 4 ATÓM 1027 CG1 VAL 137 19.728 17.634 42401 1,000 12:55 Anisa 1027 CG1 VAL 137 1371 1508 1892 182 185 111 ATÓM 1028 CG2 VAL 137 19.355 19.607 43.852 1,000 11:35 Anisa 1028 CG2 VAL 137 1461 1281 1572 182 -254 288 ATÓM 1029 C VAL 137 21.100 19.241 40.435 1,000 12:48 Anisa 1029 C VAL 137 1202 1428 2113 150 -16 8 5 ATÓM 1030 0 VAL 137 22057 18.462 40287 1,000 3.13 Anisa 1030 0 VAL 137 1021 1683 2249 149 1 14 6 ATÓM 1031 N LEU 138 20.309 19.562 39.401 1,000 10:28 Anisa 1031 N LEU 138 1198 881 1829 -15 158 226 ATÓM 1032 CA LEU 138 20.571 19.029 38066 1,000 12:48 Anisa 1032 CA LEU 138 1312 1408 2024 110 273-5 5 ATÓM 1033 CB LEU 138 19.398 19.358 37.130 1,000 i 11.81 Anisa 1033 CB LEU 138 1260 1586 1642 -20 383 4 3 ATÓM 1034 CG LEU 138 18.036 18.726 37457 1,000 i 10.77 Anisa 1034 CG LEU 138 1391 1397 1304 -83 219 213 ATÓM 1035 CD1 LEU 138 16.916 19.324 36596 1 .OOC 1 12.72 Anisa 1035 CD1 LEU 138 1416 1587 1829 -59 -25 173 ATÓM 1036 CD2 LEU 138 18.052 17.207 37.320 1,000 1 4.3 2 Anisa 1036 CD2 LEU 138 1986 1390 2065 -79 296 370 ATÓM 1037 C LEU 138 21.903 19.525 37.505 1.000 1 3.6 1 Anisa 1037 C LEU 138 1305 2026 1840 -65 174 5

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT'GB98'03860

- 124 -

ATÓM 1038 0 LEU 1 3S 22.695 18.760 36.920 1. 000 14.97 Anisa 1038 0 LEU 13S 1125 2247 23 13 105 ^ 34 1 7 7 ATÓM 1039 N ARG 139 22nd 184 20.816 37 .614 1,000 1 3. 2 ó Anisa 1039 N ARG 139 1432 2046 1561 -155 219 317 ATÓM 1040 CA ARG 139 23.397 21. 372 37.085 1,000 14.71 Anisa 1040 C A ARG 139 1648 1941 2000 -27 502 447 ATÓM 1041 C ARG 139 24.636 20.815 37.775 1,000 15:16 Anisa 1041 C ARG 139 1425 2101 2235 -158 324 116 ATÓM 1042 0 ARG 139 25.650 20.495 37.166 1,000 18:15 Anisa 1042 0 ARG 139 1628 2581 2688 18 612 ! 3 3 9 ATÓM 1043 CB ARG 139 23.394 22.926 37.206 1,000 19.67 Anisa 1043 CB ARG 139 1749 1923 3803 -196 186 252 ATÓM 1044 CG ARG 139 24.418 23.487 36.237 1,000 8.66 Anisa 1044 CG ARG 139 3924 2584 4383 -2,305 883 - 5 6 3 ATÓM 1045 CD ARG 139 24.245 24.997 36.111 1,000 9.58 Anisa 1045 CD ARG 139 6801 2389 5849 -3273 119 - 3 0 7 ATÓM in 1046 NE ARG 139 24.910 25.660 37.210 1. 000 4 7.91 Anisa in 1046 NE ARG 139 9548 2435 6222 -2157 -1331 - 7 0 8 ATÓM 1047 CZ ARG 139 24.493 26.682 37.928 1,000 5.42 Anisa 1047 CZ ARG 139 6941 4516 5802 -882 -2118 1 2 3 ATÓM 1048 NH1 ARG 139 23.316 27.273 37.722 1,000 64.33 Anisa 1048 NH1 ARG 139 7248 8153 9039 93 -2965 - 9 8 0 0 ATÓM 1049 NH2 ARG 139 25.309 27.109 38.888 1,000 3 2.62 Anisa 1049 NH2 ARG 139 5020 4758 2616 -2,746 590 167 ATÓM 1050 N ALA 140 24.562 20.684 39096 1,000 14.85 Anisa 1050 N ALA 140 1287 2204 2151 -517 -26 - 4 6 ATÓM in 1051 CA ALA 140 25.730 20.257 39.856 1,000 15.80 Anisa in 1051 CA ALA 140 989 2649 2366 -309 -9 -401 ATÓM 1052 CB ALA 140 25.444 20.442 41.330 1,000 19:36 Anisa 1052 CB ALA 140 2685 2447 2222 243 -435 - 4 8 0 ATÓM 1053 C ALA 140 26.111 18.806 39.584 1,000 16.86 Anisa 1053 C ALA 140 1555 2795 2054 12 -187 - 4 5 8 ATÓM 1054 0 ALA 140 27.258 18.403 39.796 1,000 18.90 Anisa 1054 0 ALA 140 1538 2686 2958 -21 60145 ATÓM 1055 N THR 141 25147 18.025 39098 1,000 17:53 Anisa 1055 N THR 141 1779 2532 2350 -528 218 -108 ATÓM 1056 CA THR 141 25.340 16.625 38.765 1,000 15:59 Anisa 1056 CA THR 141 1256 2401 2268 -192 -95 291 ATÓM 1,057 CB THR 141 24.207 15.735 39.343 1,000 14.77 Anisa 1,057 CB THR 141 1238 2200 2172 155 282 301 ATÓM 1058 OG1 THR 141 22.946 16.168 38.849 1,000 12:47 Anisa 1058 OG1 THR 141 1249 1565 1926 -31 295 476 ATÓM 1059 CG2 THR 141 24.167 15.818 40.859 1,000 14.82 Anisa 1059 CG2 THR 141 1394 2077 2160 135 -47 177 ATÓM 1060 C THR 141 25.423 16.374 37257 1,000 16:11 Anisa 1060 C THR 141 1732 2046 2343 303 583 325 ATÓM 1061 0 THR 141 25.432 15.235 36778 1,000 17:55 Anisa 1061 0 THR 141 1991 2104 2573 237 555 249 ATÓM 1062 N GLY 142 25.474 17.416 36.446 1,000 17.74 Anisa 1062 N GLY 142 2127 2197 2416 303 260 501 ATÓM 1063 CA GLY 142 25.611 17.263 34.987 1,000 17:32 Anisa 1063 CA GLY 142 1642 2494 2447 -160 453 517 ATÓM 1064 C GLY 142 24.426 16.556 34.358 1,000 16:37 Anisa 1064 C GLY 142 1619 1893 2710 261 473 4 2 ATÓM 1065 0 GLY 142 24.654 15.824 33.379 1,000 18:43 Anisa 1065 0 GLY 142 2243 2558 2201 57 798 163 ATÓM 1066 N THR 143 23.232 16.738 34.907 1,000 13.99 Anisa 1066 N THR 143 1531 1429 2356 83,430,350 ATÓM 1067 CA THR 143 22.049 16.003 34.472 1 .000 14.69 Anisa 1067 CA THR 14 3 1768 1591 2223 8,342 9 3 ATÓM 1068 C B THR 14 3 21.208 15.584 35.700 1. 000 15:52

SUBSTY SHEET (RULE 26)

WO 99/33994

PCT / G B9S'03860

- 125 -

ANISOU 106S CB THR 143 1457 1653 2785 55419 529 ATÓM 1069 OG1 THR 143 22037 14.784 36.573 1,000 -Γ4 »6 3 ANISOU 1069 OG1 THR 143 129ó 1792 2471 52 434 369 ATÓM 1070 CG2 THR 143 20.044 14.738 35231 1.000 1 4.2 4 ANISOU 1070 CG2 THR 143 1761 1981 1669 3 379 192 ATÓM 1071 C THR 143 21.135 16.785 33.532 1,000 1 3.9 6 ANISOU 1071 C THR 143 1553 1708 2D44 128,479 - 1 3 1 ATÓM 1072 ABOUT THR 143 20.642 17.828 3 3.923 1,000 1 5.6 5 ANISOU 1072 ABOUT THR 143 2374 1580 19 95 315 487 5 5 ATÓM 1073 N GLU 144 20.928 16.279 32.322 1.000 15.32 ANISOU 1073 N GLU 144 1734 1904 2284 -156 260 - 2 7 1 ATÓM 1074 CA GLU 144 19.917 16.693 32.362 1,000 1 7.3 0 ANISOU 1074 CA GLU 144 1686 2470 24:17 -376 152 1 0 6 ATÓM 1075 C GLU 144 18.774 15.693 33.292 1,000 1 6.8 4 ANISOU 1075 C GLU 144 1633 2380 23 86 -298 313 - 2 ATÓM 1076 ABOUT GLU 144 18.922 14.631 3C.680 1,000 1 6.7 1 ANISOU 1076 ABOUT GLU 144 1470 2057 2821 -43,610 5 8 ATÓM 1077 CB GLU 144 20.539 16.856 29.970 1,000 2 1.9 1 ANISOU 1077 CB GLU 144 2747 3417 2162 -1508 31 -8 ATÓM 1078 CG GLU 144 19.568 17.063 28.825 1,000 3 7.9 3 ANISOU 1078 CG GLU 144 6652 4374 3385 - 2057 - 2082 1 7 6 7 ATÓM 1079 CD GLU 144 19.293 18.507 28.466 1.000 43.55 ANISOU 1079 CD GLU 144 7869 4258 4419 -2497 -2259 2 1 2 9 ATÓM 1080 OE1 GLU 144 19.602 19.365 29.326 1,000 5 1.8 1 ANISOU 1080 OE1 GLU 144 9843 4613 5230 - 3180 - 832 1 1 2 6 ATÓM 1081 OE2 GLU 144 18766 18.798 27.367 1.000 40.12 ANISOU 1081 OE2 GLU 144 5551 6029 3652 -285 -115 2 5 6 0 ATÓM 1082 N PRO 145 17.620 15.959 31908 1.000 1 4.2 9 ANISOU 1082 N PRO 145 1634 1364 2432 -4 208 265 ATÓM 1083 CD PRO 145 17.256 17.136 32.718 1.000 14.14 ANISOU 1083 CD PRO 145 1735 1778 1859 -56 32 1 6 7 ATÓM 1084 CA PRO 145 16.507 15,000 31 807 1.000 13.72 ANISOU 1084 CA PRO 145 1484 1391 2337 65 173 4 6 6 ATÓM 1085 CB PRO 145 15.406 15.701 32606 1.000 14.2 0 ANISOU 1085 CB PRO 145 1459 1636 2302 161 -41 2 8 8 ATÓM 1086 CG PRO 145 16.132 16.608 33.561 1.000 1 4.4 3 ANISOU 1086 CG PRO 145 1796 2007 1679 -23 -42 ATÓM 1087 C PRO 145 16.076 14.794 30.372 1.00015.18 ANISOU 1087 C PRO 145 1745 1665 2359 -192 231 2 8 6 ATÓM 1088 ABOUT PRO 145 16.178 15.685 29.509 1,000 1 5.4 0 ANISOU 1088 ABOUT PRO 145 2430 1511 1910 -85,613-1,5 ATÓM 1089 N ASP 146 15.544 13.613 30.070 1.000 15.79 ANISOU 1089 N ASP 146 2019 1611 2367 -191 667 8 1 ATÓM 1090 CA ASP 146 14918 13.366 28.773 1.000 16.74 ANISOU 1090 CA ASP 146 2095 1759 2506 -348 575-7 7 ATÓM 1091 CB ASP 146 14.300 11.966 28727 1.000 18.99 ANISOU 1091 CB ASP 146 2508 1729 2977 -323 780 - 3 4 9 ATÓM 1092 CG ASP 146 13.504 11.784 27.444 1.000 27.04 ANISOU 1092 CG ASP 146 4012 2450 3813 -720 -229-8 0 5 ATÓM 1093 OD1 ASP 146 12.295 12.121 27409 1.000 38.65 ANISOU 1093 OD1 ASP 146 3943 4889 5852 -595 -1282 3 2 3 ATÓM 1094 OD2 ASP 146 14.091 11.311 26.466 1,000 3 9.9 5 ANISOU 1094 OD2 ASP 146 6913 5052 3214 16 0 - 1 1 8 3 ATÓM 1095 C ASP 146 13.860 14.441 28.552 1,000 1 6.6 5 ANISOU 1095 C ASP 146 2461 1904 1961 -128 580 - 3 0 ATÓM 1096 ABOUT ASP 146 13.041 14.605 29.457 1.000 15.67 ANISOU 1096 ABOUT ASP 146 2110 1935 19 08 -334 381 - 4 2 0 ATÓM 1097 N GLY 147 13.871 15.149 27.429 1,000 2 0.60 ANISOU 1097 N GLY 147 3484 2416 19 27 -26,419 1 2 9 ATÓM 1098 CA GLY 147 12.903 16.212 27155 1,000 1 8.0 6 ANISOU 1098 CA GLY 147 2771 2451 163 8 -381 98 9 3

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 126- ATÓM 1099 C GLY 147 13.361 17.574 27.609 1. 000 1 S. 7 3 Anisa 1099 C GLY 147 2836 2195 2085 -524 -I43 527 ATÓM 1100 0 GLY 147 12.676 18.570 27 .282 1,000 18:34 Anisa 1100 0 GLY 147 2865 2416 1687 -413 -72 389 ATÓM 1101 N GLY 148 14.498 17.634 28.316 1,000 16:35 Anisa 1101 N GLY 148 2936 1506 1772 -157 141 8 8 ATÓM 1102 CA GLY 148 15.116 18.889 28747 1,000 15:34 Anisa 1102 CA GLY 148 2723 1279 18 2 9 55 45C 1-26 ATÓM 1103 C GLY 148 14.768 19.339 30.144 1,000 12.97 Anisa 1103 C GLY 148 2231 1416 1280 -93 -62 407 ATÓM 1104 0 GLY 148 13.769 18.930 30771 1,000 13.79 Anisa 1104 0 GLY 148 2301 1376 1561 -164 87 3 2 3 ATÓM 1105 N VAL 149 15.604 20.224 30.718 1,000 12.81 Anisa 1105 N VAL 149 1815 1366 1686 155 -31 238 ATÓM 1106 CA VAL 149 15.388 20.724 32.079 1,000 11.81 Anisa 1106 CA VAL 149 1333 1390 1765 54 -92 ! 1 2 9 ATÓM 1107 CB VAL 149 16.594 21.636 32.480 1,000 11.97 Anisa 1107 CB VAL 149 1136 1696 1717 -100 246 124 ATÓM 1108 CG1 VAL 149 16.358 22.336 33.802 1,000 15:26 Anisa 1108 CG1 VAL 149 1941 1922 1936 -195 54 - 2 2 3 ATÓM 1109 CG2 VAL 149 17.868 20.794 32538 1,000 17:21 Anisa 1109 CG2 VAL 149 1231 2045 3265 45 102 - 0 0 3 ATÓM 1110 C VAL 149 14.101 21.482 32.280 1,000 11:32 Anisa 1110 C VAL 149 1186 1303 1813 -78 131 479 ATÓM 1111 0 VAL 149 13.378 21.218 33.253 1,000 12:35 Anisa 1111 0 VAL 149 1664 1423 1608 -71 230 1 6 7 ATÓM 1112 N GLU 150 13.752 22463 31.460 1,000 11.96 Anisa 1112 N GLU 150 1347 1453 1746 29 -36 4 2 0 ATÓM 1113 CA GLU 150 12.592 ' 23.286 31.815 1,000 10.90 Anisa 1113 CA GLU 150 1623 1359 1159 118 0 4 0 5 ATÓM 1114 CB GLU 150 12.608 24.601 30.999 1,000 17.60 Anisa 1114 CB GLU 150 2530 1470 2687 181 -161 907 ATÓM 1115 CG GLU 150 13.811 25.488 31314 1,000 17.86 Anisa 1115 CG GLU 150 2744 797 3246 246 434 2 0 2 ATÓM 1116 CD GLU 150 13.956 25.929 32.738 1,000 19:47 Anisa 1116 CD GLU 150 3018 1353 3027 -97 -84 6 6 2 ATÓM 1117 OE1 GLU 150 12.951 26.005 33475 1,000 18:21 Anisa 1117 OE1 GLU 150 3035 1512 2373 -178 -321 536 ATÓM 1118 OE2 GLU 150 15.109 26.237 33122 1,000 22:59 Anisa 1118 OE2 GLU 150 2993 1664 3927 -38 -150 284 ATÓM 1119 C GLU 150 11.277 22.533 31.705 1,000 12:22 Anisa 1119 C GLU 150 1429 1540 1676 235 147 - 5 ATÓM 1120 0 GLU 150 10.341 22.757 32.530 1,000 13:44 Anisa 1120 0 GLU 150 1739 1474 1894 315 470 288 ATÓM 1121 N ALA 151 11.118 21.625 30.742 1,000 11.88 Anisa 1121 N ALA 151 1783 1255 1477 94 45 2 5 3 ATÓM 1122 CA ALA 151 9881 20.844 30.698 1,000 13.82 Anisa 1122 CA ALA 151 1744 2054 1454 -100 -413 396 ATÓM 1123 CB ALA 151 9.739 20.094 29.390 1,000 14.89 Anisa 1123 CB ALA 151 1489 2318 1851 22 -270 - 3 5 ATÓM 1124 C ALA 151 9.792 19.864 31.867 1,000 12.71 Anisa 1124 C ALA 151 1448 1463 1920 93 41 4 2 4 ATÓM 1125 0 ALA 151 8.655 19.580 32.280 1,000 14.69 Anisa 1125 0 ALA 151 1535 2114 1932 -242 204 - 1 0 7 ATÓM 1126 N PHE 152 10.925 19.401 32.410 1,000 11.73 Anisa 1126 N PHE 152 1598 1259 1598 120 9 2 7 1 ATÓM 1127 C A PHE 152 10.890 18.554 33.602 1,000 10.61 Anisa 1127 CA PHE 152 1444 1061 1526 -33 33 1 6 0 ATÓM 1128 CB PHE 152 12.293 17.981 33.820 1,000 10:23 Anisa 1128 CB PHE 152 1317 1132 1437 -144 207 410 ATÓM 1129 CG PHE 152 12.517 17.187 35.095 1,000 10:36

SUBSTTTUTE SHEET (RULE 26)

WO 99/33094

PCT / GB9SO3860

- 127 -

Anisa 1129 CG PHE 152 1388 ATÓM 1130 CD1 PHE 152 12.036 Anisa 1130 CD1 PHE 152 1479 ATÓM 1131 CD2 PHE 152 13.229 Anisa 1131 CD2 PHE 152 1489 ATÓM 1132 CE1 PHE 152 12.252 Anisa 1132 CE1 PHE 152 1400 ATÓM 1133 CE2 PHE 152 13.431 Anisa 1133 CE2 PHE 152 1709 ATÓM 1134 CZ PHE 152 12.932 Anisa 1134 CZ PHE 152 1651 ATÓM 1135 C PHE 152 10.430 Anisa 1135 C PHE 152 1754 ATÓM 1136 ABOUT PHE 152 9728 Anisa 1136 ABOUT PHE 152 1672 ATÓM 1137 N LEU 153 10.809 Anisa 1137 N LEU 153 2030 ATÓM 1138 CA LEU 153 10.532 Anisa 1138 CA LEU 153 1890 ATÓM 1139 CB LEU 153 11.654 Anisa 1139 CB LEU 153 1691 ATÓM 1140 CG LEU 153 13.059 Anisa 1140 CG LEU 153 1762 ATÓM 1141 CD1 LEU 153 14.027 Anisa 1141 CD1 LEU 153 1609 ATÓM 1142 CD2 LEU 153 13.185 Anisa 1142 CD2 LEU 153 3091 ATÓM 1143 C LEU 153 9179 Anisa 1143 C LEU 153 1728 ATÓM 1144 ABOUT LEU 153 8.709 Anisa 1144 ABOUT LEU 153 1617 ATÓM 1145 N ASP 154 8.568 Anisa 1145 N ASP 154 1643 ATÓM 1146 CA ASP 154 7195 Anisa 1146 CA ASP 154 1862 ATÓM 1147 CB ASP 154 6.995 Anisa 1147 CB ASP 154 2091 ATÓM 1148 CG ASP 154 5.534 Anisa 1148 CG ASP 154 2323 ATÓM 1149 ODL ASP 154 4685 Anisa 1149 ODL ASP 154 2164 ATÓM 1150 OD2 ASP 154 5.168 Anisa 1150 OD2 ASP 154 2989 ATÓM 1151 C ASP 154 6.294 Anisa 1151 C ASP 154 1594 ATÓM 1152 ABOUT ASP 154 6043 Anisa 1152 ABOUT ASP 154 2143 ATÓM 1153 N CYS 155 5.891 Anisa 1153 N CYS 155 1425 ATÓM 1154 CA CYS 155 5.446 Anisa 1154 CA CYS 155 1294 ATÓM 1155 CB CYS 155 6635 Anisa 1155 CB CYS 155 1276 ATÓM 1156 SG CYS 155 7.316 Anisa 1156 SG CYS 155 1376 ATÓM 1157 C CYS 155 4 .138 Anisa 1157 C CYS 155 1301 ATÓM 1158 0 CYS 155 3215 Anisa 1158 ABOUT CYS 155 1349 ATÓM 1159 N GLU 156 4021 Anisa 1159 N GLU 156 1263

1149 1399 -34 147 276 15.896 35.229 1,000 UL., 4 1047 1743 114 - 10 3 5 6 7 17.701 36.154 1 ·. 000 11:21 1449 1319 85 174 151 15.163 36.380 1,000 10.80 1234 1467 249 -111 373 16.992 37.341 1,000 11.82 1622 11ooo -276 414 250 15.717 37 .457 1,000 11.97 1604 12 93 -255 296 170 19.292 34 858 1,000 12:24 1168 1730 -10 338 8 4 18.729 35.726 1,000 11:49 1142 1550 200 109 277 20.575 34.997 1,000 11.86 1236 1240 -6 73 15 6 21.386 36.155 1,000 11.99 1229 1437 -165 308 8 5 22.420 36353 1,000 12.81 1381 1794 -72 97-40 21.910 36.592 1,000 12.87 1645 1483 146 269 6 4 23.081 36.611 1,000 15.99 2006 2462 -49 450 - 4 4 1 21.158 37.914 1-000 19:37 2462 1806 809 275 540 22.084 36.L23 1,000 12.96 1253 1943 -336 360-4 4 22.506 37.193 1,000 13:24 1302 2109 -443 481 - 18 2 22.203 34.955 1,000 13:29 1457 195L. 60 517 '280 22.671 34.764 1,000 14:21 1255 2280 313 631 683 23.269 33573 1,000 18:38 2156 2738 328 727 1 4 7 5 23.367 32.529 1,000 22.95 3543 2855 676 430 1 5 0 1 23.607 33.820 1,000 2 0.85 2368 3389 895 477 1 1 4 4 23.254 31.702 1,000 24.33 3146 3110 228 48 112 8 21.455 34.985 1,000 11:22 1403 1265 123 147 410 20.729 34.015 1,000 13:31 1728 1186 427 219 170 21.220 36.233 1,000 9.91 1098 1243 -76 186 2 7 19.881 36627 1,000 9:41 1168 1115 -13 154 172 19.171 37.269 1,000 10.64 1015 1753 28 -51-12 12 2 19.819 38.797 1,000 1.12 1554 1633 -195 -199 9 5 19.885 37.4.23 1,000 9.66 1355 1013 115 146 216 20645 37.064 1,000 11.61 1386 1676 130 116 294 19.033 38.442 1. 000 10:26 1495 1139 -29 168 299

SUBSimrTE SHEET

WO 99/33994

PCT / GB98'03860

- 128 -

ATÓM 1160 C A GLU Anisa 1160 C A GLU ATÓM 1161 CB GLU Anisa 1161 CB GLU ATÓM 1162 CG GLU Anisa 1162 CG GLU ATÓM 1163 CD GLU Anisa 1163 CD GLU ATÓM 1164 OE1 GLU Anisa 1164 OE1 GLU ATÓM 1165 OE2 GLU Anisa 1165 OE2 GLU ATÓM 1166 C GLU Anisa 1166 C GLU ATÓM 1167 0 GLU Anisa 1167 0 GLU ATÓM 1168 N PRO Anisa 1168 N PRO ATÓM 1169 CD PRO Anisa 1169 CD PRO ATÓM 1170 CA PRO Anisa 1170 CA PRO ATÓM 1171 CB PRO Anisa 1171 CB PRO ATÓM 1172 CG PRO Anisa 1172 CG PRO ATÓM 1173 C PRO Anisa 1173 C PRO ATÓM 1174 0 PRO Anisa 1174 0 PRO ATÓM 1175 N LEU Anisa 1175 N LEU ATÓM 1176 CA LEU Anisa 1176 CA LEU ATÓM 1177 CB LEU Anisa 1177 CB LEU ATÓM 1178 CG LEU Anisa 1178 CG LEU ATÓM 1179 CD1 LEU Anisa 1179 CD1 LEU ATÓM 1180 CD2 LEU Anisa 1180 CD2 LEU ATÓM 1181 C LEU Anisa 1181 C LEU ATÓM 1182 0 LEU Anisa 1182 0 LEU ATÓM 1183 N LEU Anisa 1183 N LEU ATÓM 1184 CA LEU Anisa 1184 CA LEU ATÓM 1185 CB LEU Anisa 1185 CB LEU ATÓM 1186 CG LEU Anisa 1186 CG LEU ATÓM 1187 CD1 LEU Anisa 1187 CD1 LEU ATÓM 1188 CD2 LEU Anisa 1188 CD2 LEU ATÓM 1189 C LEU Anisa 1189 C LEU ATÓM 1190 0 LEU

156 2,778 18.787 39.173 1. 000 4.9 156 9981161 1278 -7 δ -3 ^ L2.3 6 156 2,300 17.391 38.772 1. 000 11.63 156 1187 1348 1885 -67 -135 -190 156 1,841 17.282 37326 1. 000 14:29 156 1741 1640 2049 -628 -508 5 0 156 0.502 17.949 37.039 1,000 17.90 156 1772 2692 2336 -365 -685 1 3 7 156 -0,220 18.241 38.024 1,000 19:17 156 1429 2973 2884 -632 -270 2 5 4 156 0136 18.198 35858 1,000 2 2.03 156 2449 3269 · 2653 -243 -721 924 156 2,961 18.942 40677 1,000 9.21 156 1166 1135 1197 -26 239 183 156 2.828 17.997 41476 1,000 11:22 156 1631 1199 1434 103 162 431 157 3,337 20.158 41.118 1,000 10:29 157 1329 1201 1381 -109 2112 3 157 3. 527 21.407 40359 1,000 10:17 157 1381 1093 1391 -40 -30 2 1 157 3.618 20.363 42.553 1,000 10:28 157 1160 1354 1391 -12 -61 6 4 157 4173 21.805 42.590 1,000 12:44 157 1832 1567 1330 -397 20 5 8 157 3.475 22.471 41.429 1,000 10:44 157 1469 1259 1237 -388 166-1 157 2,387 20.269 43.450 1,000 10.83 157 1206 1554 1357 -89 -60 7 6 157 1.247 20.422 42.992 1,000 11:38 157 1157 1742 1426 -93 -64 3 3 158 2.561 19.988 44.742 1,000 9.91 158 1011 1308 1447 -86 -53 151 158 1,524 19.940 45.764 1,000 10.85 158 1319 1461 1344 -387 -2-3 158 1,152 18.482 46.078 1,000 3.11 158 1280 1447 1464 -251 99 9 3 158 0111 18.239 47.155 1,000 1.12 158 1271 1497 1795 -303 241 128 158 -1,212 18.826 46.736 1,000 16:21 158 1224 2249 2685 -111 41 - 2 4 9 158 -0.086 16.736 47.397 1,000 17:17 158 2656 1542 2325 -254 1273 174 158 1,997 20.626 47.048 1,000 11:22 158 1496 1366 1402 110 -304 5 158 3,056 20.201 47539 1,000 11:28 158 1283 1368 1635 20 -260 7 5 159 1.234 21.599 47.548 1,000 10.86 159 1103 1744 1278 68 -180-7 0 159 1,540 22.278 48.797 1,000 11.62 159 1247 1761 1407 -59 -68 -18 0 159 1494 23802 48.640 1,000 12:44 159 1624 1747 1354 -209 -73 - 3 3 159 1.633 24635 49.934 1,000 12.83 159 1600 1698 1576 246 - 54 - 2 1 5 159 2,947 24.435 50.651 1,000 14:28 159 2019 2250 1158 177 -292 104 159 1.442 26.134 49.640 1,000 13:33 159 1802 172 1 1543 87 -87-2 159 0537 21. 846 49.868 1,000 11:24 159 1393 1474 1404 -174 -9-2 2 7 1 159 -0,665 21.940 49.620 1,000 13.70

SUBSTTTUTE SHEET (RULE 26)

XVO 99/33994

PCT / GB9SO3860

- 129 -

Anisa 1190 ABOUT LEU 159 1354 2395 14 5 -328 34–2 ó 9 ATÓM 1191 N ARG 160 1.013 21. 3S5 51.010 1.0 00-1.4 ». 5 9 Anisa 1191 N ARG 160 1737 2569 1239 -390 -128-2 ATÓM 1192 CA ARG 160 0158 21.030 52.153 1,000 13.94 Anisa 1192 C A ARG 160 1265 2631 1402 157 -137 9 2 ATÓM 1193 CS ARG 160 0161 19.528 52343 1,000 1 S. 2 0 Anisa 1193 CB ARG 160 1932 2645 2 338 -301 32193 ATÓM 1194 CG ARG 160 -0,423 18.661 51.252 1,000 2 5.12 Anisa 1194 CG ARG 160 3451 2902 3191 -653 -787 2 3 ATÓM 1195 CD ARG 160 -0,765 17.301 51.831 1,000 3 1.98 Anisa 1195 CD ARG 160 4825 3598 3 ' ^? 29 -1994 -905 321 ATÓM 1196 NE ARG 160 -1,284 16.322 50.896 1,000 6.15 Anisa 1196 NE ARG 160 3392 2957 3 5 87 -739 -1056 310 ATÓM 1197 CZ ARG 160 -0,970 15.044 50.779 1,000 2 5.30 Anisa 1197 CZ ARG 160 3195 3390 3C28 94 -785,295 ATÓM 1198 NH1 ARG 160 -0,063 14.433 51.552 1,000 3 1.26 Anisa 1198 NH1 ARG 160 3654 4142 4080 -629 -1089 2 0 5 5 ATÓM 1199 NH2 ARG 160 -1,572 14.308 49.850 1,000 8.82 Anisa 1199 NH2 ARG 160 4020 3122 3807 -13 -966-9 0 ATÓM 1200 C ARG 160 0649 21669 53.447 1,000 15:12 Anisa 1200 C ARG 160 1649 2863 1232 104 -66 125 ATÓM 1201 ABOUT ARG 160 1,804 21.556 53.863 1,000 9.17 Anisa 1201 ABOUT ARG 160 1291 3411 1791 -400 74-8 1 2 ATÓM 1202 N PHE 161 -0,258 22.369 54.114 1,000 14.95 Anisa 1202 N PHE 161 1512 2506 16o0 -253 -8 - 1 4 7 ATÓM 1203 CA PHE 161 -0.036 22.949 55427 1,000 13:27 Anisa 1203 CA PHE 161 1600 1681 17 (50 -9 -249-4 4 ATÓM 1204 CB PHE 161 -0,587 24,381 55.472 1,000 16.82 Anisa 1204 CB PHE 161 1594 1947 2851 384 58 6 4 ATÓM 1205 CG PHE 161 -0,317 25.109 56771 1,000 22:56 Anisa 1205 CG PHE 161 2464 2424 36 & 4 -39 790 -1067 ATÓM 1206 CD1 PHE 161 -1,175 25.010 57.849 1,000 26.03 Anisa 1206 CD1 PHE 161 3353 2919 3620 267 1106 - 7 0 0 ATÓM 1207 CD2 PHE 161 0822 25.901 56.885 1,000 25.34 Anisa 1207 CD2 PHE 161 2353 3265 4011 -179 -161 -7 3 7 ATÓM 1208 CE1 PHE 161 -0,943 25.660 59.051 1,000 30.50 Anisa 1208 CE1 PHE 161 4784 3324 3481 -972 1456 - 6 0 0 ATÓM 1209 CE2 PHE 161 1061 26.553 58.080 1,000 6.10 Anisa 1209 CE2 PHE 161 2546 3067 4302 -129 281 -1127 ATÓM 1210 CZ PHE 161 0.199 26.438 59.164 1,000 3 0.06 Anisa 1210 CZ PHE 161 3839 3197 4386 -152 773 - 6 7 7 ATÓM 1211 C PHE 161 -0,737 22.073 56.447 1,000 13.93 Anisa 1211 C PHE 161 1842 1946 1503 -334 -277 - 2 3 0 ATÓM 1212 0 PHE 161 -1,916 21.843 56.270 1,000 18:26 Anisa 1212 ABOUT PHE 161 2000 3277 16 62 -744 -399 475 ATÓM 1213 N ARG 162 -0.090 21.631 57.503 1,000 16:29 Anisa 1213 N ARG 162 2063 2516 1610 -937 -523 7 7 ATÓM 1214 CA ARG 162 -0,635 20.719 58.483 1,000 15.62 Anisa 1214 CA ARG 162 1772 2512 1650 -519 -266 7 6 ATÓM 1215 C ARG 162 -0,476 21.312 59.890 1,000 17:48 Anisa 1215 C ARG 162 1855 3131 1656 -603 -186 - 7 6 ATÓM 1216 ABOUT ARG 162 0609 21.734 60.251 1,000 17:23 Anisa 1216 ABOUT ARG 162 1928 3063 1557 -771 -42 - 16 0 ATÓM 1217 CB ARG 162 0081 19.374 58.458 1,000 2 1.99 Anisa 1217 CB ARG 162 3309 2318 2727 -272 -737-2 ATÓM 1218 CG ARG 162 -0,573 18.322 59.348 1,000 2 6.07 Anisa 1218 CG ARG 162 3488 2375 4041 489 655 280 ATÓM 1219 CD ARG 162 -0,231 16.896 58. 886 1 .OOC 125.85 Amis 1219 CD ARG 162 3106 2221 4495 418 -2 2 3 8 ATÓM 1220 NE ARG 162 -0,943 15.916 59.698 1 .OOC 8.83 Anisa 1220 NE ARG 162 4379 2437 4139 -181 332-1 7 7

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S'03860

- 130 -

ATÓM 1221 CZ ARG 162 -0,642 14.638 59.679 Anisa 1221 CZ ARG 162 4271 2497 3868 ATÓM 1222 NH1 ARG 162 0.429 14.119 59.273 Anisa 1222 NH1 ARG 162 3200 3167 3742 ATÓM 1223 NH2 ARG 162 -1,408 13. 883 60658 Anisa 1223 NH2 ARG 162 3807 3522 5663 ATÓM 1224 N TYR 163 -1,570 21.296 60622 Anisa 1224 N TYR 163 1803 2865 1705 ATÓM 1225 CA TYR 163 -1,627 21.749 61997 Anisa 1225 CA TYR 163 1819 2770 1766 ATÓM 1226 CB TYR 163 -2,712 22.804 62116 Anisa 1226 CB TYR 163 2479 2560 2175 ATÓM 1227 CG TYR 163 -3,173 23.206 63488 Anisa 1227 CG TYR 163 2573 3821 2544 ATÓM 1228 CD1 TYR 163 -2,316 23848 64.367 Anisa 1228 CD1 TYR 163 3613 5005 3466 ATÓM 1229 CE1 TYR 163 -2,731 24.222 65.625 Anisa 1229 CE1 TYR 163 5855 5676 3950 ATÓM 1230 CD2 TYR 163 -4,459 22.965 63931 Anisa 1230 CD2 TYR 163 3307 5654 3408 ATÓM 1231 CE2 TYR 163 -4,902 23.332 65189 Anisa 1231 CE2 TYR 163 5626 6630 4080 ATÓM 1232 CZ TYR 163 -4,017 23.960 66025 Anisa 1232 CZ TYR 163 6281 5799 4075 ATÓM 1233 OH TYR 163 -4,380 24.351 67274 Anisa 1233 OH TYR 163 8167 6831 3569 ATÓM 1234 C TYR 163 -1,935 20.551 62.896 Anisa 1234 C TYR 163 2872 2353 1575 ATÓM 1235 ABOUT TYR 163 -2,933 19.858 62653 Anisa 1235 ABOUT TYR 163 2694 2130 2060 ATÓM 1236 N PHE 164 -1,112 20.326 63.898 Anisa 1236 N PHE 164 2516 2621 1826 ATÓM 1237 CA PHE 164 -1,340 19.381 64984 Anisa 1237 CA PHE 164 4176 2692 2038 ATÓM 1238 CB PHE 164 -0,073 18.617 65327 Anisa 1238 CB PHE 164 4594 2824 2470 ATÓM 1239 CG PHE 164 0407 17.669 64231 Anisa 1239 CG PHE 164 4118 3639 3263 ATÓM 1240 CD1 PHE 164 1,224 18.118 63205 Anisa 1240 CD1 PHE 164 3040 4013 3249 ATÓM 1241 CD2 PHE 164 0051 16.332 64.240 Anisa 1241 CD2 PHE 164 3935 3139 3704 ATÓM 1242 CE1 PHE 164 1.657 17.248 62223 Anisa 1242 CE1 PHE 164 2730 3926 4034 ATÓM 1243 CE2 PHE 164 0.459 15.464 63.250 Anisa 1243 CE2 PHE 164 4719 3694 3635 ATÓM 1244 CZ PHE 164 1,276 15.924 62234 Anisa 1244 CZ PHE 164 3827 3808 3862 ATÓM 1245 C PHE 164 -1,775 20.160 66228 Anisa 1245 C PHE 164 3541 4049 1777 ATÓM 1246 ABOUT PHE 164 -0,889 20.713 66885 Anisa 1246 0 PHE 164 3520 4167 2019 ATÓM 1247 N PRO 165 -3,058 20.293 66527 Anisa 1247 N PRO 165 3641 5095 3513 ATÓM 1248 CA PRO 165 -3,486 21.012 67720 Anisa 1248 CA PRO 165 3570 5737 3225 ATÓM 1249 C PRO 165 -2,854 20.429 68986 A1JIS0U 1249 C PRO 165 4355 6808 3457 ATÓM 1250 ABOUT PRO 165 -2,551 19.230 69034 Anisa 1250 ABOUT PRO 165 9948 7012 3507 ATÓM 1251 CB PP.O 165 -5,001 20.820 67769

1.000 27.99

- 1 7 9 - ^ 2 N 4

1,000 2 5.6 1

-91 -126 - 2 7 8

1.000 3 4.2 0

-987 702 7 8 0

1,000 1 6.7 7

-484 -194 7 4

1,000 1 6.7 3

-692 -51 0 4

1.000 1 8.9 9

-427 -303 - 2

1.000 23.52

-16 -335-868

1,000 3 1.8 0

-1152 304 - 2 3 3 8

1.000 40.74

-1906 976 - 3 1 1 5

1,000 3 2.5 5

-1066 639 2 3 4 0

1,000 4 2.9 9

-2352 1989 2 9 4 9

1.000 42.52

-1721 1943 - 3 7 1 5

1.000 48.87

-269 1801 - 3 0 5 2

1,000 17.9 0

-894 -465 -

1.000 18.12

-732 -615 6 6

1.000 18.32

-614 -402-9 0

1,000 2 3.44

-727 -669 2 9

1,000 2 6.02

-459 -822 3 7 9

1,000 2 9.00

-518 -427 - 2 5 4

1,000 2 7.1 1

-198 -821 4

1.000 28.37

473 30 - 6 4

1,000 2 8 .13

-43 -229 6

1.000 31.71

-293,657 - 3 8 3

1,000 3 0.2 6

300 126

1.000 24.65

-1025 -455 3 6

1,000 2 5.5 4

-921 -440 - 2 6 7

1,000 3 2.2 4 -1894 266 - 6 8 0

1,000 3 2.9 8

-1272 397 - 3 2 2

1,000 3 8.4 8

-1872 40343

1,000 5 3.8 7

-957 692 1 7 5 0. 000 3 7.7 7

SUBSTTRTTE SHEET (RULE 26)

WO 99/33994 rCT / GB98'03860

- 131 -

Anisa 1251 CB PRO 165 3 6 3 0 6479 4 227 ATÓM 1252 CG PRO 165 -5,417 20048 No. 6. 5 ó 9 Anisa 1252 CG PRO 165 3 34 1 6449 3948 ATÓM 1253 CD PRO 165 -4,197 19 Dec 816 65 .734 Anisa 1253 CD PRO 165 3440 6296 3828 ATÓM 1254 N LEU 178 4459 8087 66987 Anisa 1254 N LEU 178 4509 3338 5918 ATÓM 1255 C A LEU 178 4 .994 9.117 66116 Anisa 1255 CA LEU 178 3397 3170 4312 ATÓM 1256 CB LEU 178 5882 8.534 65027 Anisa 1256 CB LEU 178 3497 3245 4588 ATÓM 1257 CG LEU 178 7.245 7.948 65348 Anisa 1257 CG LEU 178 3557 2950 4674 ATÓM 1258 CD1 LEU 178 7859 7367 64073 Anisa 1258 CD1 LEU 178 2972 4524 4 '> 13 ATÓM 1259 CD2 LEU 178 8.208 8964 65937 Anisa 1259 CD2 LEU 178 5303 3695 6850 ATÓM 1260 C LEU 178 3.885 9.909 65420 Anisa 1260 C LEU 178 2107 3534 4686 ATÓM 1261 ABOUT LEU 178 2.845 9.351 65086 Anisa 1261 ABOUT LEU 178 2407 4624 8C16 ATÓM 1262 N ARG 179 4.128 11.200 65.160 Anisa 1262 N ARG 179 2220 3437 4089 ATÓM 1263 CA ARG 179 3,231 11.973 64321 Anisa 1263 CA ARG 179 1860 3289 4365 ATÓM 1264 C ARG 179 3.297 11.572 62852 Anisa 1264 C ARG 179 2158 2721 4434 ATÓM 1265 ABOUT ARG 179 2.295 11.687 62139 Anisa 1265 ABOUT ARG 179 2545 3242 5079 ATÓM 1266 CB ARG 179 3,517 13.480 64451 Anisa 1266 CB ARG 179 3980 3317 3561 ATÓM 1267 CG ARG 179 2.936 14.092 65724 Anisa 1267 CG ARG 179 3817 3725 3852 ATÓM 1268 CD ARG 179 3307 15.570 65757 Anisa 1268 CD ARG 179 4457 3675 3 84 0 ATÓM 1269 NE ARG 179 2,925 16.126 67058 Anisa 1269 NE ARG 179 7035 3190 4144 ATÓM 1270 CZ ARG 179 2897 17.425 67292 Anisa 1270 CZ ARG 179 8420 3029 3532 ATÓM 1271 NH1 ARG 179 3.213 18286 66331 Anisa 1271 NH1 ARG 179 11745 4676 6273 ATÓM 1272 NH2 ARG 179 2,548 17.896 68457 Anisa 1272 NH2 ARG 179 5661 3832 3094 ATÓM 1273 N MET 180 4.455 11,099 62.424 Anisa 1273 N MET 180 2013 2457 3674 ATÓM 1274 CA MET 180 4695 10.539 61108 Anisa 1274 CA MET 180 2346 1965 3315 ATÓM 1275 C MET 180 5802 9,482 61182 Anisa 1275 C MET 180 2251 2080 2254 ATÓM 1276 ABOUT MET 180 6.894 9.757 61677 Anisa 1276 ABOUT MET 180 2237 2019 2781 ATÓM 1277 CB MET 180 5,041 11.646 60136 Anisa 1277 CB MET 180 2571 2321 3709 ATÓM 1278 CG MET 180 5065 11.367 58678 Anisa 1278 CG MET 180 3918 3095 3588 ATÓM 1279 SD MET 180 4. 945 12.838 57629 Anisa 1279 SD MET 180 2936 2942 3626 ATÓM 1280 CE MET 180 4 .385 12.010 56. 147 Anisa 1280 CE MET 180 5917 3450 4690 ATÓM 1281 N ALA 181 5467 8.295 60.680 Anisa 1281 N ALA 181 2144 2139 2174

-1488 3S0-7 1 7 1,000- ££ _in 1 6 -518 -349 - 3 9 S 1,000 3 5.70 -1656 -5 - 6 0 4 1,000 6.23 -26 1216 1175 1,000 8.63 377 1344 401 1,000 3 0.08 760 752-6 6 0 1,000 9.43 667 371-9 7 9 1,000 2.13 586 810-7 9 0 1,000 4 1.71 356 -1655 - 1 1 5 < 1,000 2 7.18 -175 1776 833 1,000 3 9.60 -1253 1289 2 1 8 3 1,000 25.65 -216 878 741 1,000 25.04 69 641 . 1 5 1,000 24.51 39 99 -89 1,000 28.60 441 -332 - 2 6 6 1,000 28.58 -110 -844 5 7 1,000 30.01 -957 - 3 7 2 1,000 31.51 -1514 - 3 3 8 1,000 37.82 153 -310-1 1,000 39.43 -479 580 400 1,000 59.73 -1045 3178 1 7 2 2 1,000 3 3.13 275 -1462 - 1 7 3 1,000 21:43 -395 107 - 2 2 2 1,000 2 0.07 -349 -300 151 1,000 17:33 -332 -86 337 1,000 18:52 -398 -79 5 2 1,000 2 2.64 -197 -549 683 1,000 7.90 -453 -654 913 1,000 2 5.01 -399 124 851 1,000 3 7.00 -258 -2675 1 2 0 4 1,000 16.99 -90 -558 299

SUBSTTrUTE SHEET (RULE 26)

WO 99/33994 to CT / G B98 / 03860

- 132 -

ATÓM 1282 C A ALA 181 6. 396 Anisa 1282 C A ALA 181 2275 ATÓM 1283 CB ALA 181 5668 Anisa 1283 CB ALA 181 2857 ATÓM 1284 C ALA 181 7.576 Anisa 1284 C ALA 181 2223 ATÓM 1285 ABOUT ALA 181 7458 Anisa 1285 ABOUT ALA 181 2268 ATÓM 1286 N PRO 182 8698 Anisa 1286 N PRO 182 2517 ATÓM 1287 CD PRO 182 8.983 Anisa 1287 CD PRO 182 2321 ATÓM 1288 C A PRO 182 9,865 Anisa 1288 CA PRO 182 2573 ATÓM 1289 CB PRO 182 10.914 Anisa 1289 CB PRO 182 2570 ATÓM 1290 C G PRO 182 10.479 Anisa 1290 CG PRO 182 2301 ATÓM 1291 C PRO 182 9.541 Anisa 1291 C PRO 182 2230 ATÓM 1292 ABOUT PRO 182 8.920 Anisa 1292 ABOUT PRO 182 2301 ATÓM 1293 N HIS 183 9969 Anisa 1293 N HIS 183 1737 ATÓM 1294 CA HIS 183 9733 Anisa 1294 CA HIS 183 1413 ATÓM 1295 CB HIS 183 8.300 Anisa 1295 CB HIS 183 1399 ATÓM 1296 CG HIS 183 8168 Anisa 1296 CG HIS 183 1349 ATÓM 1297 CD2 HIS 183 8.259 Anisa 1297 CD2 HIS 183 1684 ATÓM 1298 ND1 HIS 183 7989 Anisa 1298 ND1 HIS 183 1901 ATÓM 1299 CE1 HIS 183 7943 Anisa 1299 CE1 HIS 183 1939 ATÓM 1300 NE2 HIS 183 8101 Anisa 1300 NE2 HIS 183 1560 ATÓM 1301 C HIS 183 10.749 Anisa 1301 C HIS 183 1446 ATÓM 1302 ABOUT HIS 183 11.433 Anisa 1302 ABOUT HIS 183 1496 ATÓM 1303 N TYR 184 10.849 Anisa 1303 N TYR 184 1453 ATÓM 1304 CA TYR 184 11.483 Anisa 1304 CA TYR 184 1475 ATÓM 1305 CB TYR 184 12.628 Anisa 1305 CB TYR 184 1631 ATÓM 1306 CG TYR 184 12.368 Anisa 1306 CG TYR 184 1680 ATÓM 1307 CD1 TYR 184 12.156 Anisa 1307 CD1 TYR 184 1663 ATÓM 1308 CE1 TYR 184 11.911 Anisa 1308 CE1 TYR 184 1960 ATÓM 1309 CD2 TYR 184 12.333 Anisa 1309 CD2 TYR 184 1252 ATÓM 1310 CE2 TYR 184 12.102 Anisa 1310 CE2 TYR 184 1944 ATÓM 1311 CZ TYR 184 11.898 Anisa 1311 CZ TYR 184 1717 ATÓM 1312 OH TYR 184 11.663

7. 16S 60.676 1,000 1 ó. 1 2 1958 1890 -171 - □ 4 3 6 0 2 5.891 60.279 1,000 2 0.24 2158 2673 -64 8 693 1 0 6 7409 59.738 1,000 15:43 1717 1925 -315 -369 432 8.198 58783 1,000 15:49 1761 1858 -173 -296 434 6733 59.986 1,000 3.16 1745 1829 32 -78 15 3 1 5802 61101 1,000 19.61 2908 2221 -210 -305 1 2 4 0 6.907 59.076 1,000 14.78 1336 1706 -101 -86 299 5.948 59.649 1,000 16:20 1978 1607 170 -251 7 7 5713 61066 1,000 19:28 3071 1952 -199 -245 1 0 0 0 6571 57.627 1,000 14.90 1658 1772 -421 -262 340 5573 57.249 1,000 15:38 1587 1957 -467 -482 539 7.460 56.730 1,000 12:28 1312 1617 -154 -284 156 7.354 55.300 1,000 11.90 1495 1614 -254 -352 3 5 7824 54.922 1,000 12:43 1368 1957 -128 -241 112 9.314 55089 1,000 11:36 1369 1600 -367 -296 5 6 10.374 54.249 1,000 3.12 1296 1589 -43 157 - 10 0 9.858 56.339 1,000 13:27 1439 1700 -65 267 193 11.187 56.244 1,000 12:43 1490 1296 77 -245 1 5 0 11.515 54.992 1,000 4.11 1437 1199 215 -232 4 8 8176 54.515 1,000 12:27 1639 1577 -303 -282 - 6 7 9.032 55.064 1,000 12.94 1915 1505 -558 -292 1 5 7,907 53.215 1,000 10.61 1027 1552 -41 -380 110 8,800 52.256 1,000 11:36 1104 1738 -71 -264 178 8.151 51.481 1,000 11.79 1114 1734 -62 -198 3 4 6.907 50.677 1,000 11:29 920 1688 225 -893 1 7 4 5.659 51268 1,000 11.76 928 1879 388 -487 1 9 0 4526 50.492 1,000 12.64 878 1964 173 -40 1 8 2 6949 49.279 1,000 11:13 1302 1674 109 -283 9 3 5.834 48.502 1,000 12.93 1422 1546 49 -384 7 3 4.611 49.121 1,000 13:14 1304 1972 30 -611 6 6 3 .490 48.343 1,000 15:45

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994 rCT / GB9S'03S60

- 133 -

Anisa 1312 OH TYR 184 202S ATÓM 1313 C TYR 184 10.447 Anisa 1313 C TYR 184 1445 ATÓM 1314 0 TYR 184 9.362 Anisa 1314 0 TYR 184 1305 ATÓM 1315 N ASP 185 10.7S4 Anisa 1315 N ASP 185 1581 ATÓM 1316 CA ASP 185 9.861 Anisa 1316 CA ASP 185 1089 ATÓM 1317 CB ASP 185 9. 934 Anisa 1317 CB ASP 185 1427 ATÓM 1318 CG ASP 185 9.540 Anisa 1318 CG ASP 185 1797 ATÓM 1319 OD1 ASP 185 9.681 Anisa 1319 OD1 ASP 185 2050 ATÓM 1320 OD2 ASP 185 9.114 Anisa 1320 OD2 ASP 185 1805 ATÓM 1321 C ASP 185 10.098 Anisa 1321 C ASP 185 1036 ATÓM 1322 0 ASP 185 11.234 Anisa 1322 0 ASP 185 1167 ATÓM 1323 N LEU 186 9.038 Anisa 1323 N LEU 186 1211 ATÓM 1324 CA LEU 186 9.124 Anisa 1324 CA LEU 186 1641 ATÓM 1325 CB LEU 186 8.030 Anisa 1325 CB LEU 186 1652 ATÓM 1326 CG LEU 186 7989 Anisa 1326 CG LEU 186 1408 ATÓM 1327 CD1 LEU 186 6896 Anisa 1327 CD1 LEU 186 1900 ATÓM 1328 CD2 LEU 186 9.356 Anisa 1328 CD2 LEU 186 1438 ATÓM 1329 C LEU 186 9.024 Anisa 1329 C LEU 186 1327 ATÓM 1330 0 LEU 186 8768 Anisa 1330 0 LEU 186 2067 ATÓM 1331 N SER 187 9264 Anisa 1331 N SER 187 1546 ATÓM 1332 CA SER 187 9.401 Anisa 1332 CA SER 187 1427 ATÓM 1333 CB SER 187 9221 Anisa 1333 CB SER 187 1105 ATÓM 1334 OG SER 187 10.430 Anisa 1334 OG SER 187 1343 ATÓM 1335 C SER 187 10.774 Anisa 1335 C SER 187 1447 ATÓM 1336 0 SER 187 11.684 Anisa 1336 0 SER 187 1577 ATÓM 1337 N MET 188 10.962 Anisa 1337 N MET 188 1419 ATÓM 1338 CA MET 188 12.267 Anisa 1338 CA MET 188 1394 ATÓM 1339 CB MET 188 12.128 Anisa 1339 CB MET 188 1523 ATÓM 1340 CG MET 188 13.385 Anisa 1340 CG MET 188 1403 ATÓM 1341 SD MET 188 14.687 Anisa 1341 SD MET 188 1619 ATÓM 1342 CE MET 188 16.061 Anisa 1342 CE MET 188 1862

1471 2 37 3 42-476 -247 9 390 51.314 1.000-1.1 ,. 5 0 1215 ľ.7 09 -1S7 -201 3 4 8 8797 51.089 1,000 11.75 1308 1853 -106 -171 4 2 7 10.557 50743 1,000 10.79 1069 1449 -141 -132 1 1 8 11.218 49.815 1,000 9.10 1093 1277 -326 23 2 0 6 12.743 49.886 1,000 10:13 1095 1327 -298 -177 1 7 7 13.388 51.185 1,000 11.79 1350 1333 -250 -149 1 1 14.638 51278 1,000 13.79 1316 1875 135 -52 - 2 6 12.755 52.189 1,000 13:31 1848 1405 -411 -63 1 0 5 10.759 48.371 1,000 9:44 1150 1401 R309 -26 1 0 0 10.469 48.005 1,000 10.64 1376 1500 -127 -35 - 2 0 7 10.684 4 7.568 1,000 9.10 1186 1437 -272 -177 - 5 8 10.312 4 <5.161 1,000 10.60 986 1401 -239 -52 - 4 4 9.295 45.798 1,000 11:32 922 1721 -111 17 -479 7.977 46.602 1,000 12.60 1039 2340 -263 -200 - 1 6 7 7.064 46.028 1,000 16.64 1373 3 04 9 -634 -398-1 7.332 46.629 1,000 13.84 1245 2Ξ · 75 -155 442 2 8 3 11.521 45 .223 1,000 10.90 1211 1603 -3 -451 11.406 44.031 1,000 13.60 1608 1494 -211 -321 1 0 3 12.705 45.734 1,000 10.71 1129 1393 -76 -282 3 1 8 13.943 44.998 1,000 10:49 1191 1370 195 -107 4 8 8 15.103 46.002 1,000 10:56 1048 1857 298 161 5 3 2 14918 46726 1,000 1.13 1432 2169 -132 -295 201 14.062 44.336 1,000 10:47 861 1669 135 -3 14 5 13.246 44.513 1,000 10:54

799 1629 183 -91 - 7 7

15.095 43.502 1,000 9.78 977 1318 147 44 7 4 15.584 43.065 1,000 9.94 941 1441 182 58 3 7 16.543 41.891 1,000 10.89 838 1774 98 48 2 2 7 17.258 41.470 1,000 11:40 1172 1756 46 -51 2 14 16.134 40.891 1,000 12.71 1272 194 0 139 137 198 17.267 40.790 1,000 13.86 1399 200 3 -2 911 .-90

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT7GB9S'03860

- 134 -

ATÓM 1 34 3 C MET 188 12.946 Anisa 1343 C MET 18S 1325 ATÓM 1344 ABOUT MET 188 13.971 Anisa 1344 ABOUT MET 188 1288 ATÓM 1345 N VAL 189 12362 Anisa 1345 N VAL 189 1290 ATÓM 1346 C A VAL 189 12.745 Anisa 1346 CA VAL 189 1209 ATÓM 1347 CB VAL 189 13.618 Anisa 1347 CB VAL 189 1288 ATÓM 1348 CG1 VAL 189 14. 953 Anisa 1348 CG1 VAL 189 1334 ATÓM 1349 CG2 VAL 189 12.899 Anisa 1349 CG2 VAL 189 1715 ATÓM 1350 C VAL 189 11.469 Anisa 1350 C VAL 189 1089 ATÓM 1351 ABOUT VAL 189 10.405 Anisa 1351 ABOUT VAL 189 1153 ATÓM 1352 N THR 190 11.609 Anisa 1352 N THR 190 1273 ATÓM 1353 C A THR 190 10.565 Anisa 1353 CA THR 190 1350 ATÓM 1354 CB THR 190 10.194 Anisa 1354 CB THR 190 1231 ATÓM 1355 OG1 THR 190 9662 Anisa 1355 OG1 THR 190 1333 ATÓM 1356 CG2 THR 190 9.038 Anisa 1356 CG2 THR 190 1121 ATÓM 1357 C THR 190 11.058 Anisa 1357 C THR 190 1257 ATÓM 1358 ABOUT THR 190 12.149 Anisa 1358 ABOUT THR 190 1322 ATÓM 1359 N LEU 191 10.313 Anisa 1359 N LEU 191 1319 ATÓM 1360 CA LEU 191 10.691 Anisa 1360 CA LEU 191 1259 ATÓM 1361 CB LEU 191 10.604 Anisa 1361 CB LEU 191 1203 ATÓM 1362 CG LEU 191 11,897 Anisa 1362 CG LEU 191 1898 ATÓM 1363 CD1 LEU 191 12.333 Anisa 1363 CD1 LEU 191 1685 ATÓM 1364 CD2 LEU 191 11.717 Anisa 1364 CD2 LEU 191 2310 ATÓM 1365 C LEU 191 9.798 Anisa 1365 C LEU 191 1275 ATÓM 1366 ABOUT LEU 191 8.560 Anisa 1366 0 LEU 191 1276 ATÓM 1367 N ILE 192 10,394 Anisa 1367 N ILE 192 1115 ATÓM 1368 CA ILE 192 9671 Anisa 1368 CA ILE 192 1071 ATÓM 1369 CB ILE 192 9. 927 Anisa 1369 CB ILE 192 2099 ATÓM 1370 CG2 ILE 192 9221 Anisa 1370 CG2 ILE 192 2479 ATÓM 1371 CG1 ILE 192 9.512 Anisa 1371 CG1 ILE 192 2633 ATÓM 1372 CD1 ILE 192 9.845 Anisa 1372 CD1 ILE 192 5869 ATÓM 1373 C ILE 192 9. 966

16.217 44.291 1,000 12:13 1586 1698 169 -Ί. & -285 15 Dec 727 44804 1. 000 11:52 1553 1535 144 132 8 7 17.290 44.838 1,000 10:00 1217 1292 53 -175 6 17.894 46.099 1,000 9.70 1,057 1420 -212 -45 - 1 9 19.154 45. 979 1,000 9.97 1103 1398 -238 129 189 18.837 45.266 1,000 13:45 1410 2368 -236 390 143 20.289 45.264 1,000 12:24 1242 1693 -25 150 295 18.245 46.871 1,000 10:10 1600 1149 -456 -156-7 3 18.399 46.250 1,000 9:53 1249 1217 -222 -190 8 18327 48.187 1,000 8.66 895 1123 15 -202 12 7 18.771 49091 1,000 9.64 1167 1147 -11 -228-9 9 17.699 50.132 1,000 10.69 1196 1635 -300 121-5 5 16.586 49501 1,000 12:45 1341 2055 -140 -258-4 8 18.131 51019 1,000 13:59 2222 1821 -272 151 - 19 5 19.976 49.891 1,000 9.23 1096 1152 -102 -336 - 4 9 19.867 50.447 1,000 10:54 1292 1390 -5 -359 - 21.064 49.978 1,000 10:23 1167 1401 -71 -178 - 1 3 3 22.241 50.770 1,000 10:19 1176 1438 -294 - 1 4 2 23.511 49.910 1,000 11:52 1185 1990 -118 -601 3 2 23.898 49.167 1,000 13:23 1710 1419 -391 -359 9 7 22.794 48.218 1,000 15:25 2018 2091 -476 -214 - 3 0 4 25.231 48.448 1,000 17:46 2044 2281 -14 16 6 0 4 22328 52006 1,000 11.93 1677 1579 -190 - 3 7 2 22.262 51868 1,000 13:49 2173 1676 1 -192 - 6 0 0 22.483 53.190 1,000 6.11 1603 1487 -111 -92 - 1 0 7 22.539 54443 1,000 11:13 1638 1521 11 -174 - 1 4 9 21.304 55.330 1,000 12.94 1586 1232 -65 -9 - 2 3 4 21.428 56.673 1,000 6.16 1983 1641 -206 426 - 2 1 4 20.028 54.590 1,000 15:51 4 1658 1601 -400 -48 - 1 7 4 18765 55.339 1,000 2 5.71 1608 2290 -175 -1566 - 3 0 0 23.809 55.253 1. 000 11:47

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 135 -

Anisa 1373 C ILE 192 1330 1603 1427 -4 -2ľ ! 2 - 1 2 2 ATÓM 1374 0 ILE 192 11.123 24. 106 55567 1,000 • «, 3 3 Anisa 1374 0 ILE 192 1344 1738 1981 -96 -289 - 2 9 ATÓM 1375 N GLN 193 8.904 24.525 55.602 1. 000 15.78 Anisa 1375 N GLN 193 1316 2462 2219 -64 -5-9 7 5 ATÓM 1376 C A GLN 193 8.987 25.653 55.533 1,000 14:56 Anisa 1376 C A GLN 193 1582 1858 2 391 212 -304- 5 2 9 ATÓM 1377 CB GLN 193 8.449 26.975 56020 1,000 0.03 Anisa 1377 CB GLN 193 2226 2203 318 0 318 -329 142 ATÓM 1378 CG GLN 193 9.203 27684 54914 1,000 2 3.86 Anisa 1378 CG GLN 193 3399 2492 3 2.74 313 44 2 8 0 ATÓM 1379 CD GLN 193 8665 29.079 54.675 1,000 2 2.92 Anisa 1379 CD GLN 193 3250 2363 3097 78 -477 205 ATÓM 1380 ΟΞ1 GLN 193 7603 29.292 54.099 1,000 7.68 Anisa 1380 OE1 GLN 193 4175 3310 3C31 552 -1215 2 9 ATÓM 1381 NE2 GLN 193 9.411 30.075 55 .134 1,000 2 7.01 Anisa 1381 NE2 GLN 193 3187 2667 4408 -440 124 1 7 ATÓM 1382 C GLN 193 8.216 25.265 57.804 1,000 15:14 Anisa 1382 C GLN 193 1945 1827 1982 136 -174-7 2 2 ATÓM 1383 0 GLN 193 7.147 24.662 57.714 1,000 27.80 Anisa 1383 0 GLN 193 2523 6225 1817 -1586 -592 235 ATÓM 1384 N GLN 194 8.714 25.552 58.978 1,000 19.80 Anisa 1384 N GLN 194 2994 2502 2025 -632 -752 3 3 ATÓM 1385 CA GLN 194 8.100 25.080 60.213 1,000 2.89 Anisa 1385 CA GLN 194 3961 2626 2110 493 -20 5 2 ATÓM 1386 C GLN 194 7.763 26.236 61141 1,000 27.79 Anisa 1386 C GLN 194 4886 2757 2916 823 25-2 2 6 2 ATÓM 1387 0 GLN 194 8424 27.258 60983 1,000 3 0.03 Anisa 1387 0 GLN 194 4727 3168 3516 368 -259-9 1 0 ATÓM 1388 CB GLN 194 9086 24.170 60.950 1,000 2 3.97 Anisa 1388 CB GLN 194 3952 3133 2021 846 483 352 ATÓM 1389 CG GLN 194 9.398 22.835 60.314 1,000 21.94 Anisa 1389 CG GLN 194 2740 3238 2358 683 -182 - 10 ATÓM 1390 CD GLN 194 10.546 22.148 61052 1,000 2 0.51 Anisa 1390 CD GLN 194 2450 3433 1911 509 -321- 4 2 9 ATÓM 1391 OE1 GLN 194 11.707 22.142 60627 1,000 2 0.80 Anisa 1391 OE1 GLN 194 2245 2996 2662 -171 -382 - 6 8 1 ATÓM 1392 NE2 GLN 194 10.223 21.585 62197 1,000 24.91 Anisa 1392 NE2 GLN 194 2539 3902 3023 210 -365 760 ATÓM 1393 N THR 195 6.817 26.035 62030 1,000 3 2.47 Anisa 1393 N THR 195 5716 2729 3891 1095 1056 - 6 1 7 ATÓM 1394 CA THR 195 6.588 26.708 63282 1,000 3 5.83 Anisa 1394 CA THR 195 6329 3539 3748 1011 999-7 2 2 ATÓM 1395 CB THR 195 5263 27.492 63357 1,000 37.96 Anisa 1395 CB THR 195 5756 4304 4365 647 2095 - 1 ATÓM 1396 OGL THR 195 4191 26.576 63604 1,000 8.36 Anisa 1396 OGL THR 195 6874 6076 5423 -806 2581 - 1 8 3 ATÓM 1397 CG2 THR 195 4958 28175 62033 1,000 4.54 Anisa 1397 CG2 THR 195 2944 7471 6510 -872 -963 621 ATÓM 1398 C THR 195 6,590 25.684 64429 1,000 4 8.86 Anisa 1398 C THR 195 10133 4924 3 5 03 -321 -1356 2 2 1 ATÓM 1399 0 THR 195 6122 24.544 64293 1,000 64.12 Anisa 1399 0 THR 195 13267 4150 694 5 -264 -4542 1 6 8 2 ATÓM 1400 N PHE 201 12.035 21.374 72.205 1,000 7 1.12 Anisa 1400 N PHE 201 13961 9034 4028 -5,932 -1657 - 1 7 4 1 ATÓM 1401 CA PHE 201 11.775 20.053 71629 1. 000 4 9.44 Anisa 1401 C A PHE 201 7918 7543 3 3 26 -3,128 1316 - 1 4 8 7 ATÓM 1402 CB PHE 201 10.469 19.464 72.:.81 1,000 7.85 Anisa 1402 CB PHE 201 7119 6892 416 « -1,869 1937 - 1 8 9 9 ATÓM 1403 CG PHE 201 10,130 18.113 71.5 4 5 1,000 6.41 Anisa 1403 CG PHE 201 6643 6596 43 96 -2,038 1879 - 1 4 9 6

SUBSTmiTE SHEET (RULE 25)

WO 99/33994

PCT / GB98 / 03860

- 136 -

ATÓM 1404 CD1 PHE 201 10.738 16.954 71991 1.000 50.03 Anisa 1404 CD1 PHE 201 7982 6634 4393 -2326-IOS2 - 9 9 1 ATÓM 1405 CD2 PHE 201 9.220 18.001 70.513 1,000 4 2.6 3 Anisa 1405 CD2 PHE 201 5458 6427 4313 -1097 2449 - 2 2 6 7 ATÓM 1406 CE1 PHE 201 10.434 15.739 71417 1,000 4 9.9 5 Anisa 1406 CE1 PHE 201 8275 6464 4240 -2048 227 - 7 1 6 ATÓM 1407 CE2 PHE 201 8.901 16.783 69.934 1.000 4 1.3 8 Anisa 1407 CE2 PHE 201 6016 5946 3762 -578 2006 1 8 4 4 ATÓM 1408 CZ PHE 201 9.515 15.636 70392 1.000 44.74 Anisa 1408 CZ PHE 201 7075 6261 3663 -1063 1020 9 9 5 ATÓM 1409 C PHE 201 11.722 20.110 70107 1,000 4 2.4 2 Anisa 1409 C PHE 201 6324 6442 3351 -1963 717 - 1 4 4 1 ATÓM 1410 ABOUT PHE 201 11.007 20.941 69536 1,000 4 7.7 9 Anisa 1410 ABOUT PHE 201 9668 4400 4090 -762 691 - 2 4 1 5 ATÓM 1411 N VAL 202 12.477 19.232 69449 1,000 3 4.04 Anisa 1411 N VAL 202 4525 5852 2558 -1949 7 - 4 2 5 ATÓM 1412 CA VAL 202 12.535 19.245 67993 1,000 2 5.0 9 Anisa 1412 CA VAL 202 3221 3752 2558 -1041 -182 9 9 ATÓM 1413 CB VAL 202 13.988 19.286 67489 1,000 2 2.8 8 Anisa 1413 CB VAL 202 2832 3430 2432 -577 -691-1 9 8 ATÓM 1414 CG1 VAL 202 14.053 19.387 65965 1.000 26.02 Anisa 1414 CG1 VAL 202 3821 3594 2470 -958 35-2 7 7 ATÓM 1415 CG2 VAL 202 14.771 20.443 68078 1.000 24.69 Anisa 1415 CG2 VAL 202 3043 3473 2867 -786 -410 - 3 0 0 ATÓM 1416 C VAL 202 11.798 18.035 67421 1,000 2 0.69 Anisa 1416 C VAL 202 3027 2810 2023 -649 58 6 1 5 ATÓM 1417 ABOUT VAL 202 12.288 16.914 67581 1.000 26.08 Anisa 1417 ABOUT VAL 202 3294 3219 3396 -136,452 8 8 4 ATÓM 1418 N SER 203 10.662 18.234 66766 1,000 2 0.2 1 Anisa 1418 N SER 203 3100 2794 1787 -414 25-1 5 2 ATÓM 1419 CA SER 203 9.820 17.192 66218 1,000 2 0.3 7 Anisa 1419 CA SER 203 3149 2709 1884 -355 128 - 2 5 6 ATÓM 1420 CB SER 203 8437 17.779 65896 1.000 24.72 Anisa 1420 CB SER 203 2726 4106 2558 -178,369 -1,015 ATÓM 1421 OG SER 203 7841 18.239 67097 1.000 31.80 Anisa 1421 OG SER 203 3328 5782 2974 -457 1175-1,104 ATÓM 1422 C SER 203 10.367 16.524 64958 1.00019.13 Anisa 1422 C SER 203 2580 2647 2040 -339 170 - 2 3 4 ATÓM 1423 ABOUT SER 203 10.279 15.302 64832 1.000 17.01 Anisa 1423 ABOUT SER 203 2311 2625 1527 -414 206-1 8 ATÓM 1424 N LEU 204 10902 17.259 63998 1.000 16.16 Anisa 1424 N LEU 204 2142 1976 2024 72 77 - 2 9 2 ATÓM 1425 CA LEU 204 11.403 16.679 62740 1.000 14.07 Anisa 1425 CA LEU 204 1670 1626 2049 -22 -24-2 2 8 3 ATÓM 1426 CB LEU 204 11.269 17.704 61618 1.000 13.80 Anisa 1426 CB LEU 204 1549 1763 1931 -249 -340 2 7 7 ATÓM 1427 CG LEU 204 11.647 17.272 60.212 1,000 1 4.1 3 Anisa 1427 CG LEU 204 1726 1722 1919 -253 -482- 4 1 2 ATÓM 1428 CD1 LEU 204 10.770 16.134 59.680 1,000 1 8.7 6 Anisa 1428 CD1 LEU 204 2579 2895 1654 -1297 -927 - 1 0 7 ATÓM 1429 CD2 LEU 204 11.609 18.478 59.255 1.000 1 6.2 0 Anisa 1429 CD2 LEU 204 1987 2095 2074 66 75 - 1 2 3 ATÓM 1430 C LEU 204 12.832 16.140 62885 1.000 1 4.8 1 Anisa 1430 C LEU 204 1734 1748 2144 9 -199 - 2 6 0 ATÓM 1431 0 LEU 204 13.699 16.853 63397 1.000 15.52 Anisa 1431 0 LEU 204 1833 1789 2274 -59 -435-4 ATÓM 1432 N GLN 205 13.065 14.900 62469 1.000 1 4.4 2 Anisa 1432 N GLN 205 1847 1804 1827 188 -120 - 1 5 3 ATÓM 1433 CA GLN 205 14.288 14.143 62574 1.000 12.76 Anisa 1433 CA GLN 205 1777 1655 1419 43 -347-1 1 3 ATÓM 1434 C GLN 205 14.622 13.434 61260 1.000 11.12

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 137 -

Anisa 1434 C GLN 205 1412 1474 ATÓM 1435 ABOUT GLN 205 13.707 12.927 Anisa 1435 ABOUT GLN 205 1622 2235 ATÓM 1436 CB GLN 205 14.164 13.062 Anisa 1436 CB GLN 205 2421 1925 ATÓM 1437 CG GLN 205 13.863 13.635 Anisa 1437 CG GLN 205 3321 2286 ATÓM 1438 CD GLN 205 15.086 14.243 Anisa 1438 CD GLN 205 3687 3465 ATÓM 1439 OE1 GLN 205 16.206 13.717 Anisa 1439 OE1 GLN 205 3350 3464 ATÓM 1440 NE2 GLN 205 14.840 15.356 Anisa 1440 NE2 GLN 205 3055 2465 ATÓM 1441 N ALA 206 15.893 13.401 Anisa 1441 N ALA 206 1523 1770 ATÓM 1442 CA ALA 206 16.335 12.649 Anisa 1442 CA ALA 206 1392 2099 ATÓM 1443 CB ALA 206 16.693 13.519 Anisa 1443 CB ALA 206 2034 2494 ATÓM 1444 C ALA 206 17.567 11.813 Anisa 1444 C ALA 206 1489 2331 atom 1445 ABOUT ALA 206 18.368 12.182 Anisa 1445 ABOUT ALA 206 1877 1772 ATÓM 1446 N GLU 207 17.707 10.712 Anisa 1446 N GLU 207 1981 2086 ATÓM 1447 CA GLU 207 18.938 9.942 Anisa 1447 CA GLU 207 2198 1938 ATÓM 1448 C GLU 207 20.082 10688 Anisa 1448 C GLU 207 1828 2037 ATÓM 1449 ABOUT GLU 207 19.948 10.953 Anisa 1449 ABOUT GLU 207 1746 2145 ATÓM 1450th CB GLU 207 18.665 8.612 Anisa 1450 CB GLU 207 3289 1794 ATÓM 1451 CG GLU 207 19.879 7737 Anisa 1451 CG GLU 207 4102 2221 ATÓM 1452 CD GLU 207 19.429 6356 Anisa 1452 CD GLU 207 5549 2024 ATÓM 1453 OE1 GLU 207 19.491 5471 Anisa 1453 OE1 GLU 207 5782 2692 ATÓM 1454 OE2 GLU 207 19.037 6.251 Anisa 1454 OE2 GLU 207 4955 5608 ATÓM 1455 N VAL 208 21.146 10.997 Anisa 1455 N VAL 208 1926 1974 ATÓM 1456 CA VAL 208 22.376 11.593 Anisa 1456 CA VAL 208 1894 2109 ATÓM 1457 CB VAL 208 22.455 13.111 Anisa 1457 CB VAL 208 2774 2148 ATÓM 1458 CG1 VAL 208 23652 13.688 Anisa 1458 CG1 VAL 208 3214 2150 ATÓM 1459 CG2 VAL 208 21.172 13.815 Anisa 1459 CG2 VAL 208 3146 1640 ATÓM 1460 C VAL 208 23.585 10.877 Anisa 1460 C VAL 208 1936 2555 ATÓM 1461 ABOUT VAL 208 23.726 10.829 Anisa 1461 ABOUT VAL 208 2436 2256 ATÓM 1462 N GLY 209 24.457 10.295 Anisa 1462 N GLY 209 1764 2445 ATÓM 1463 CA GLY 209 25.558 9.508 Anisa 1463 CA GLY 209 2171 3040 ATÓM 1464 C GLY 209 25.123 8.364 Anisa 1464 C GLY 209 2874 3156

L338 49 -46 iS - 2 1 60606 1000 * 423 ". 9 7 L449 -293 -449 - 1 4 7 63662 Ί. 000 15:57 15 68 341 151 8 3 65032 1,000 18:58 1451 689 -129 8 2 65680 1,000 2 4.33 2091 520 -499 - 5 6 0 65549 1,000 2 9.12 4251 14 -27 0 - 1 8 0 0 66378 1,000 2 3.01 32 25 335 -592 - 1 3 0 60893 1,000 12.63 1506 -251 -234 - 6 59731 1,000 13.77 1742 -522 -72 - 2 9 58.528 1,000 16:34 1682 -603 123-2 7 7 60046 1,000 15.92 22 3 0 -290 179 - 3 3 1 60908 1,000 15.86 2377 150 -357 3 0 59.305 1,000 16.98 2383 -335 348-1 8 6 Ξ9.364 1,000 20:58 3684 -164 490 - 10 0 58681 1,000 18.75 3260 272 185 558 57.503 1,000 18:23 3034 52 8 -45 58.676 1,000 2 5.81 4724 -19 82 - 1 3 5 58.429 1,000 30.08 5105 907 -948 5 5 6 57.959 1,000 9.93 3798 1179 -2099 - 1 2 58839 1,000 5.14 4879 938 -931 885 56.762 1,000 8.62 4109 135 -2494 - 3 7 6 59.414 1,000 16.97 2549 120 337 8 0 6 58.902 1,000 17.77 2748 93 500 411 59.155 1,000 16.89 1494 -372 -149 569 58.409 1,000 2 0.76 2526 -423 647 148 58.720 1,000 16:36 1431 25 98 3 5 3 59.507 1,000 2 0.29 3217 11 -58 60741 1,000 2 0.74 3187 460 206 544 58.672 1,000 18.94 2989 211 -494 1 5 59.194 1,000 24.01 3910 549 -397 7 0 9 60082 1,000 2 5.00 3470 1406 772 649

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 138-

ATÓM 1465 ABOUT GLY 209 25.850 7,934 60991 1,000 3 5.9 8 Anisa 1465 ABOUT GLY 209 4448 3946 5279 1425- 1769 ATÓM 1466 N GLY 210 23.951 7786 59869 1,000 2 5.89 Anisa 1466 N GLY 210 3802 2756 3278 52 3 899 749 ATÓM 1467 CA GLY 210 23.477 6678 60671 1,000 6.43 Anisa 1467 CA GLY 210 4479 2136 3427 1228 742 912 ATÓM 1468 C GLY 210 22.885 7.025 62016 1,000 8.45 Anisa 1468 C GLY 210 5472 2099 3237 831 1028 1 1 7 5 ATÓM 1469 ABOUT GLY 210 22.634 6098 62789 1,000 4 0.26 Anisa 1469 ABOUT GLY 210 7322 2719 5256 1881 2760 2 3 6 0 ATÓM 1470 N ALA 211 22.651 8.281 62338 1,000 2 5.78 Anisa 1470 N ALA 211 4671 2359 2763 1370 725 1 1 9 7 ATÓM 1471 CA ALA 211 22.048 8671 63613 1,000 2 3.74 Anisa 1471 CA ALA 211 2966 3156 2896 727 339 663 ATÓM 1472 CB ALA 211 23.093 9.333 64496 1,000 9.57 Anisa 1472 CB ALA 211 2957 4372 3906 834 -96 6 9 ATÓM 1473 C ALA 211 20.900 9.626 63.360 1,000 2 1.19 Anisa 1473 C ALA 211 3090 2611 2350 484 178 741 ATÓM 1474 ABOUT ALA 211 20.936 10.381 62399 1,000 2 3.91 Anisa 1474 0 ALA 211 3771 2659 2653 -30 -66 930 ATÓM 1475 N PHE 212 19.889 9629 64204 1,000 19.88 Anisa 1475 N PHE 212 2603 2577 2375 398 -128 374 ATÓM 1476 CA PHE 212 18.814 10.613 64.130 1,000 19:13 Anisa 1476 CA PHE 212 2581 2257 2432 284 -565 317 ATÓM 1477 C PHE 212 19.320 12.006 64489 1,000 2 0.00 Anisa 1477 C PHE 212 3004 2480 2115 133 -640 6 8 ATÓM 1478 ABOUT PHE 212 19.893 12.230 65569 1,000 2 1.10 Anisa 1478 ABOUT PHE 212 2497 3558 1964 -391 -406 222 ATÓM 1479 CB PHE 212 17.688 10.290 65.096 1,000 2 1.37 Anisa 1479 CB PHE 212 2553 2616 2952 293 -197 - 18 4 ATÓM 1480 CG PHE 212 17.010 8,950 64912 1,000 2 3.45 Anisa 1480 CG PHE 212 2161 3496 3253 -376 -282 - 5 5 8 ATÓM 1481 CDI PHE 212 16.369 8.377 65.990 1,000 2 3.33 Anisa 1481 CDI PHE 212 2545 3115 3206 -382 -350 - 5 0 8 ATÓM 1482 CD2 PHE 212 17.029 8.302 63687 1,000 2 5.83 Anisa 1482 CD2 PHE 212 2554 3962 3299 -622 -217-7 8 7 ATÓM 1483 CE1 PHE 212 15.730 7.149 65872 1,000 8.13 Anisa 1483 CE1 PHE 212 3784 3544 3362 -1119 96-9 7 3 ATÓM 1484 CE2 PHE 212 16.419 7.072 63569 1,000 2 3.04 Anisa 1484 CE2 PHE 212 2504 2960 3289 382 -232 - 5 5 8 ATÓM 1485 CZ PHE 212 15.781 6486 64651 1,000 7.88 Anisa 1485 CZ PHE 212 3658 3977 2957 -1072 -501-7 6 0 ATÓM 1486 N THR 213 19.076 12.936 63578 1,000 18:30 Anisa 1486 N THR 213 2690 2083 2181 149 -583-9 3 ATÓM 1487 CA THR 213 19.566 14.310 63681 1,000 17.99 Anisa 1487 CA THR 213 1976 2139 2721 230 -686-2 8 7 ATÓM 1488 CB THR 213 20.515 14.586 62498 1,000 2 0.43 Anisa 1488 CB THR 213 1798 2280 3683 140 -119-4 4 2 3 ATÓM 1489 OG1 THR 213 21.638 13.695 62629 1,000 5.33 Anisa 1489 OG1 THR 213 2571 3378 3676 925 714 2 8 ATÓM 1490 CG2 THR 213 21.087 15,985 62485 1,000 2 1.11 Anisa 1490 CG2 THR 213 1935 2667 3420 -310 -289-7 4 7 ATÓM 1491 C THR 213 18.391 15.277 63641 1,000 15:53 Anisa 1491 C THR 213 1732 2135 2032 111 -557 - 1 7 6 ATÓM 1492 ABOUT THR 213 17.533 15.195 62761 1,000 16:11 Anisa 1492 ABOUT THR 213 1742 2197 2180 -327 -669 5 6 ATÓM 1493 N ASP 214 18.362 16.199 64.590 1,000 15.60 Anisa 1493 N ASP 214 2025 2046 1857 64 -405 2 ATÓM 1494 CA ASP 214 17.380 17.256 64672 1,000 15:59 Anisa 1494 CA ASP 214 2130 1722 2072 -1010 - 2 4 2 ATÓM 1495 CB ASP 214 17.744 18.200 65822 1,000 17:13

SUBSTTrUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9SO3S60

- 139 -

Anisa 1495 CB ASP 214 2528 189 3 2086 -226 - 10 2 2 - 2 3 ATÓM 1496 CG ASP 214 17.612 17.672 67219 1.000-2.0 ,. 2 1 Anisa 1496 CG ASP 214 3138 24 95 2045 -451 -127O -14 8 ATÓM 1497 OD1 ASP 214 17.079 16.571 67460 • 1000 2 0.87 Anisa 1497 OD1 ASP 214 2778 2632 2518 -247 -506 1 5 1 ATÓM 1498 OD2 ASP 214 18.076 18.401 68127 1,000 2 8.05 Anisa 1498 OD2 ASP 214 5110 3118 2429 -257 -1997 -619 ATÓM 1499 C ASP 214 17,314 18. 146 63441 1,000 15:14 Anisa 1499 C ASP 214 2029 1822 1901 182 -574 - 3 9 9 ATÓM 1500 0 ASP 214 18349 18.552 62897 1,000 17.63 Anisa 1500 0 ASP 214 1956 2032 2710 -214 -810-1 ATÓM 1501 N LEU 215 16.105 18493 63027 1,000 14.69 Anisa 1501 N LEU 215 1936 1758 1387 38 -334 242 ATÓM 1502 CA LEU 215 15.915 19.504 6 L. 979 1,000 13:35 Anisa 1502 CA LEU 215 1820 1753 1498 89 -22 I 5 9 ATÓM 1503 CB LEU 215 15.352 18.819 60.734 1,000 14:24 Anisa 1503 CB LEU 215 1735 2167 1506 -98 75 - 3 ATÓM 1504 CG LEU 215 16.291 17.813 60056 1,000 16:39 Anisa 1504 CG LEU 215 2031 2285 1911 -340 320-4 4 2 4 ATÓM 1505 CD1 LEU 215 15.517 16.999 59.031 1,000 22.61 Anisa 1505 CD1 LEU 215 3139 2024 3427 -10 -801-8 7 7 ATÓM 1506 CD2 LEU 215 17.482 18.543 59434 1,000 6.93 Anisa 1506 CD2 LEU 215 1998 5409 2827 -1083 908 - 5 4 2 ATÓM 1507 C LEU 215 15.002 20.622 62,500 1,000 14.65 Anisa 1507 C LEU 215 1770 1607 21 90 86 -165-9 5 ATÓM 1508 0 LEU 215 13.822 20.662 62 .151 1,000 19:45 Anisa 1508 0 LEU 215 1748 2165 3476 116 -303 - 2 0 4 ATÓM 1509 N PRO 216 15.552 21.523 63314 1,000 15.99 Anisa 1509 N PRO 216 2390 1970 1715 -164 21 - 1 6 5 ATÓM 1510 CD PRO 216 16.955 21.601 63757 1,000 19:37 Anisa 1510 CD PRO 216 2900 2306 2155 -83 -790-5 5 4 8 ATÓM 1511 CA PRO 216 14.760 22.620 63846 1,000 18.68 Anisa 1511 CA PRO 216 3104 2017 1976 12 -74 _; -420 ATÓM 1512 CB PRO 216 15.649 23.227 64.949 1,000 18.63 Anisa 1512 CB PRO 216 3592 1517 1971 -120 -421 9 ATÓM 1513 CG PRO 216 17.030 22847 64581 1,000 2 2.35 Anisa 1513 CG PRO 216 3401 2426 2666 -419 -427-7 8 3 ATÓM 1514 C PRO 216 14.461 23.700 62819 1,000 18:50 Anisa 1514 C PRO 216 2921 2083 2026 58 -465 - 4 7 3 ATÓM 1515 0 PRO 216 15.024 23.854 61731 1,000 19.82 Anisa 1515 0 PRO 216 2752 2453 2325 -32 -376 1 9 ATÓM 1516 N TYR 217 13.487 24.536 63194 1,000 2 0.05 Anisa 1516 N TYR 217 3213 1981 2422 90 -482-7 1 8 ATÓM 1517 CA TYR 217 13.178 25662 62308 1,000 22.97 Anisa 1517 CA TYR 217 2849 2652 32 27 211 -1466 - 3 1 3 ATÓM 1518 C TYR 217 14.347 26.647 62283 1,000 23.92 Anisa 1518 C TYR 217 4139 2131 28 L9 -337 -1775 - 1 6 5 ATÓM 1519 0 TYR 217 15.149 26.726 63213 1,000 3 0.46 Anisa 1519 0 TYR 217 4321 3440 38 12 -1118 -2477 728 ATÓM 1520 CB TYR 217 11.891 26.314 62768 1,000 3 2.68 Anisa 1520 CB TYR 217 3958 3294 5164 1148 -874-7 8 3 ATÓM 1521 CG TYR 217 12.064 27.462 63718 1,000 4 4.77 Anisa 1521 CG TYR 217 6829 4326 5854 895 39 - 1 8 7 0 ATÓM 1522 CD1 TYR 217 11.853 28.763 63 .285 1,000 54.26 Anisa 1522 CD1 TYR 217 10311 3688 6615 -323 131 - 1 9 4 5 ATÓM 1523 CD2 TYR 217 12.428 27.243 65. 043 1,000 5 7.77 Anisa 1523 CD2 TYR 217 10635 5155 6158 -1027 -1446 -1931 ATÓM 1524 CE1 TYR 217 12.011 29.816 64174 1,000 60.33 Anisa 1524 CE1 TYR 217 11807 4345 6 7 72 -1101 -132 - 2 2 5 8 ATÓM 1525 CE2 TYR 217 12.585 28.296 65926 1,000 4.51 Anisa 1525 CE2 TYR 217 12481 5199 6 8 3 2 -1936 -1520 - 2 0 7 5

SUBSTtTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB9S / 03860

- 140 -

ATÓM 1526 CZ TYR 217 12.378 29. 586 65481 1. 000 6 4.11 Anisa 1526 CZ TYR 217 12047 5183 7129 -L460-Q17-2160 ATÓM 1527 OH TYR 217 12.536 30639 66358 1,000 6 3.69 Anisa 1527 OH TYR 217 11840 5206 7153 -18 3 2 -119 1 - 2 0 6 3 ATÓM 1528 N ARG 218 14.418 27.374 61188 1,000 2 4.08 Anisa 1528 N ARG 218 4482 1611 3055 507 -1470 - 1 4 5 ATÓM 1529 CA ARG 218 15.335 28.465 60948 1,000 3 0.71 Anisa 1529 C A ARG 218 5932 2490 3245 -5 04 -1565 382 ATÓM 1530 CB ARG 218 16.326 28.135 59.840 1. 000 3 5.08 Anisa 1530 CB ARG 218 5969 2797 4562 -1397 -779- 3 4 8 ATÓM 1531 CG ARG 218 17.401 27.114 60073 1,000 3 5.77 Anisa 1531 C G ARG 218 6009 3087 4497 -1107 -733-7 7 3 ATÓM 1532 CD ARG 218 18.658 27.775 60626 1,000 3 4.46 Anisa 1532 CD ARG 218 5680 3264 4152 -1242 -244 - 6 1 9 ATÓM 1533 ΝΞ ARG 218 19.223 28746 59709 1,000 9.51 Anisa 1533 ΝΞ ARG 218 4707 2579 3926 78 81 -629 ATÓM 1534 CZ ARG 218 20.218 28.620 58. 830 1,000 3 3.18 Anisa 1534 CZ ARG 218 5269 3166 4170 60 452 - 1 0 7 4 ATÓM 1535 NH1 ARG 218 20.839 27.452 58.709 1,000 7.44 Anisa 1535 NH1 ARG 218 4202 2881 3341 -503 -373-1 ATÓM 1536 NH2 ARG 218 20.583 29.675 58077 1,000 2 2.96 Anisa 1536 NH2 ARG 218 2327 3579 2817 233 -1117-8 7 2 ATÓM 1537 C ARG 218 14.513 29.655 60464 1,000 3 1.05 Anisa 1537 C ARG 218 7353 1949 2496 -448 -1823 197 ATÓM 1538 0 ARG 218 14.114 29.533 59.295 1,000 4 0.40 Anisa 1538 0 ARG 218 9873 2241 3235 531 -3168 - 7 2 7 ATÓM 1539 N PRO 219 14.246 30.747 61157 1,000 30.01 Anisa 1539 N PRO 219 6290 2559 2555 -499 -1839 - 2 7 4 ATÓM 1540 CD PRO 219 14597 31.043 62543 1,000 6.79 Anisa 1540 CD PRO 219 8147 2878 2954 -1,848 -2549 - 3 7 4 ATÓM 1541 C A PRO 219 13.464 31.841 60549 1,000 26.34 Anisa 1541 CA PRO 219 4421 2564 3025 -573 -988 - 3 3 0 ATÓM 1542 CB PRO 219 13.523 32.993 61563 1,000 3 2.44 Anisa 1542 CB PRO 219 5361 2891 4073 -691 -417-9 8 9 ATÓM 1543 CG PRO 219 13.947 32.372 62825 1,000 38.75 Anisa 1543 CG PRO 219 7916 3462 3344 -1981 -958 - 1 2 ATÓM 1544 C PRO 219 14.005 32.329 59.220 1,000 23.64 Anisa 1544 C PRO 219 3472 2066 3443 -161 -1028 109 ATÓM 1545 0 PRO 219 13.300 32.950 58.412 1,000 3 0.61 Anisa 1545 0 PRO 219 4358 2934 4339 -347 -1712 876 ATÓM 1546 N ASP 220 15.269 32087 58906 1,000 2 5.98 Anisa 1546 N ASP 220 3611 1756 4506 -389 -644-8 1 5 ATÓM 1547 CA ASP 220 15.847 32.660 57.705 1,000 7.96 Anisa 1547 CA ASP 220 3951 1603 5071 -364 30-8 2 4 ATÓM 1548 CB ASP 220 17.212 33.238 58.155 1,000 9.61 Anisa 1548 CB ASP 220 3549 3142 4558 -176 -326 176 ATÓM 1549 CG ASP 220 18.091 32.158 58.780 1,000 3 2.09 Anisa 1549 CG ASP 220 3706 3527 4961 625 978 615 ATÓM 1550 OD1 ASP 220 17.697 31.434 59.719 1,000 6.12 Anisa 1550 OD1 ASP 220 3013 3522 3390 -158 -289-9 7 ATÓM 1551 OD2 ASP 220 19.241 32088 58281 1,000 2 9.09 Anisa 1551 OD2 ASP 220 3714 3756 3581 304 678 - 7 1 2 ATÓM 1552 C ASP 220 16.037 31.726 56.525 1,000 5.26 Anisa 1552 C ASP 220 2508 1291 5800 354 1110-8 2 2 ATÓM 1553 0 ASP 220 16.641 32.095 55.515 1,000 8.28 Anisa 1553 0 ASP 220 4088 1665 4994 -855 298 - 4 4 4 ATÓM 1554 N ALA 221 15.500 30.510 56631 1,000 21:58 Anisa 1554 N ALA 221 2748 1770 3681 -288 178 - 6 6 1 ATÓM 1555 CA ALA 221 15.840 29.484 55658 1,000 19.81 Anisa 1555 CA ALA 221 2986 1452 3090 -342 -224 - 3 1 4 ATÓM 1556 CB ALA 221 17.130 28.800 56. 109 1. 000 19:51

SUBSTTTTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 141 -

Anisa 1556 CB ALA 221 2267 1497 3647 -648 45-7 4 6 ATÓM 1557 C ALA 221 14.718 28.469 35.489 1.000-1.1.7 1 Anisa 1557 C ALA 221 2304 1912 2512 -251 - 75 - 3 0 9 ATÓM 1558 ABOUT ALA 221 13.866 28356 56.380 ' 1,000 2 0.97 Anisa 1558 ABOUT ALA 221 3596 2029 2 344 -503 406 - 2 7 4 ATÓM 1559 N VAL 222 14.728 27756 54.378 1,000 14:22 Anisa 1559 N VAL 222 1560 1582 22 62 -76 -92-1 1 ATÓM 1560 CA VAL 222 13.823 26.617 54.160 1,000 14.89 Anisa 1560 CA VAL 222 1326 1608 2723 98 -217 - 2 0 5 ATÓM 1561 CB VAL 222 13.079 26.779 52.830 1,000 17:28 Anisa 1561 CB VAL 222 1680 1754 3133 -657 - 1 4 4 ATÓM 1562 CG1 VAL 222 13.995 26685 51.620 1,000 19:17 Anisa 1562 CG1 VAL 222 1974 2625 2686 -446 -775 150 ATÓM 1563 CG2 VAL 222 11.996 25.747 52.641 1,000 17:36 Anisa 1563 CG2 VAL 222 2185 1879 2533 -254 -362 - 3 8 ATÓM 1564 C VAL 222 14.653 25.339 54.263 1,000 12.66 Anisa 1564 C VAL 222 1136 1564 2112 -50 -225 - 3 7 8 ATÓM 1565 ABOUT VAL 222 15.828 25.320 53.893 1,000 13:12 Anisa 1565 ABOUT VAL 222 1280 1825 1881 104 -13 - 19 9 ATÓM 1566 N LEU 223 14.049 24.267 54775 1,000 12.98 Anisa 1566 N LEU 223 1123 1538 2270 -163 -370 - 4 1 6 ATÓM 1567 CA LEU 223 14.681 22.952 54749 1,000 10.70 Anisa 1567 CA LEU 223 891 1704 1472 -26 ! -98 1 - 7 ATÓM 1568 CB LEU 223 14.276 22.130 55.961 1,000 2.13 Anisa 1568 CB LEU 223 1387 1968 1593 -419 289 - 1 0 7 ATÓM 1569 CG LEU 223 14.739 20.683 56106 1,000 17:41 Anisa 1569 CG LEU 223 2434 2132 2050 -290 -478 5 6 6 ATÓM 1570 CD1 LEU 223 16.247 20.614 56204 1,000 17:20 Anisa 1570 CD1 LEU 223 2576 1518 2441 26 -989-249 ATÓM 1571 CD2 LEU 223 13.983 20.076 57.282 1,000 3 3.63 Anisa 1571 CD2 LEU 223 3981 4721 4077 -341 135 2 9 4 9 ATÓM 1572 C LEU 223 14.362 22.211 53.456 1,000 10.2 Anisa 1572 C LEU 223 1000 1265 1543 58 -318 8 8 ATÓM 1573 ABOUT LEU 223 13.206 22.160 53.088 1,000 12.86 Anisa 1573 ABOUT LEU 223 949 1945 1992 -97 -174 -372 ATÓM 1574 N VAL 224 15.406 21.675 52.798 1,000 10:55 Anisa 1574 N VAL 224 978 1070 1962 -76 -418 - 3 8 2 ATÓM 1575 CA VAL 224 15.227 20.932 51553 1,000 11.98 Anisa 1575 CA VAL 224 1376 1288 1887 -249 -278 - 3 7 2 ATÓM 1576 CB VAL 224 16.095 21461 50.391 1,000 11:23 Anisa 1576 CB VAL 224 901 1541 1824 -279 -622 9 9 ATÓM 1577 CG1 VAL 224 15.833 20.690 49.102 1,000 13:16 Anisa 1577 CG1 VAL 224 1899 1485 1615 -462 -516 8 4 ATÓM 1578 CG2 VAL 224 15.837 22.941 50.156 1,000 13.86 Anisa 1578 CG2 VAL 224 1480 1520. 2266 -135 -354 - 6 4 ATÓM 1579 C VAL 224 15.539 19.450 51786 1,000 10.87 Anisa 1579 C VAL 224 953 1275 1901 -13 342 - 4 8 4 ATÓM 1580 ABOUT VAL 224 16.646 19.148 52.201 1,000 12:57 Anisa 1580 ABOUT VAL 224 1283 1363 21:32 -175 - 154 - 2 7 4 ATÓM 1581 N PHE 22S 14.585 18.553 51.533 1,000 11.86 Anisa 1581 N PHE 225 1241 1128 2137 -15 -303-6 6 ATÓM 1582 CA PHE 225 14.811 17.130 51.412 1,000 11:38 Anisa 1582 CA PHE 225 1260 1157 1909 -22 -67 - 5 6 ATÓM 1583 CB PHE 225 13.707 16.280 52044 1,000 11:34 Anisa 1583 CB PHE 225 1117 1176 202 5 205 -213 335 ATÓM 1584 CG PHE 225 13.654 16.172 53544 1,000 11:38 Anisa 1584 CG PHE 225 965 1369 19 91 -251 -333 ATÓM 1585 CD1 PHE 225 14.685 15.653 54291 1,000 15:28 Anisa 1585 CD1 PHE 225 1771 1777 2256 -98 -853 298 ATÓM 1586 CD2 PHE 225 12.532 16.576 54254 1,000 17.91 Anisa 1586 CD2 PHE 225 1904 2748 2153 341 106 0

suBSTrrure sheet (rule 25)

WO 99/33994

PCT / GB98 / 03860

- 142-

ATÓM 1587 CE1 PHE 225 14.619 15.535 55.661 1,000 17.46 Anisa 1587 CE1 PHE 225 2449 1862 2321 -249 .. jr 95 95 6 6 6 ATÓM 1588 CE2 PHE 225 12.447 16.474 55.612 1.000 19 '. 3 5 Anisa 1588 CE2 PHE 225 2563 2678 2111 121 129-1 1 ATÓM 1589 CZ PHE 225 13.499 15.945 56.341 1.000 18:20 Anisa 1589 CZ PHE 225 2952 1641 2324 -501 -470 3 6 ATÓM 1590 C PHE 225 14.907 16.774 49.927 1.000 3.12 Anisa 1590 C PHE 225 1480 1285 1804 130 -201 4 2 ATÓM 1591 0 PHE 225 14.019 17.160 49.163 1.000 12.77 Anisa 1591 0 PHE 225 1473 14 6 6 1912 341 -119 3 8 ATÓM 1592 N CYS 226 15.940 16.032 49.521 1.000 9.62 Anisa 1592 N CYS 226 954 1403 1,196 -204 -407 2 9 ATÓM 1593 CA CYS 226 15.917 15.400 48.197 1.000 10.80 Anisa 1593 CA CYS 226 1432 1204 1468 -258 -310 - 5 9 ATÓM 1594 CB CYS 226 17.337 15.029 47.744 1.000 2.12 Anisa 1594 CB CYS 226 1539 1362 1666 -357 16 - 1 2 4 ATÓM 1595 SG CYS 226 18.426 16.490 47.554 1.000 13.74 Anisa 1595 SG CYS 226 1627 1400 2192 -341 17 1 3 9 ATÓM 1596 C CYS 226 14.998 14.178 48.256 1.000 9.86 Anisa 1596 C CYS 226 1190 1061 1495 -20 -293-1 ATÓM 1597 0 CYS 226 15.015 13.431 49.252 1.000 11:17 Anisa 1597 0 CYS 226 1181 1280 1781 -129 -435 272 ATÓM 1598 N GLY 227 14.217 13.963 47.205 1.000 10:17 Anisa 1598 N GLY 227 1428 1010 1427 -258 -271 - 3 6 ATÓM 1599 CA GLY 227 13.370 12.806 47.053 1.000 9.73 Anisa 1599 CA GLY 227 1231 860 1604 -178 -74 - 3 7 ATÓM 1600 C GLY 227 13.908 11.769 46.074 1.000 9:48 Anisa 1600 C GLY 227 1438 714 1445 16 -35 16 9 ATÓM 1601 0 GLY 227 14.935 11.961 45.402 1.000 9.86 Anisa 1601 0 GLY 227 1321 1137 1290 -104 -178 7 8 ATÓM 1602 N ALA 228 13.217 10.631 45.971 1.000 9.17 Anisa 1602 N ALA 228 1279 728 1477 109 -135 5 8 ATÓM 1603 CA ALA 228 13.650 9529 45.108 1.000 9:41 Anisa 1603 CA ALA 228 1315 887 1370 9 -74 -52 ATÓM 1604 CB ALA 228 12.727 8.296 45.256 1.000 10:50 Anisa 1604 CB ALA 228 2011 824 1155 -143 124 1 0 0 ATÓM 1605 C ALA 228 13.712 9.918 43.637 1.000 9.25 Anisa 1605 C ALA 228 1343 666 1507 -108 90 13 9 ATÓM 1606 0 ALA 228 14.493 9,305 42.895 1.000 9:48 Anisa 1606 0 ALA 228 1171 1026 1405 -88 -50 9 0 ATÓM 1607 N ILE 229 12.970 10.907 43.143 1.000 10:30 Anisa 1607 N ILE 229 1402 1004 1508 18 25 17 7 ATÓM 1608 CA ILE 229 13.074 11.311 41.727 1.000 10.87 Anisa 1608 CA ILE 229 1197 1446 1487 -2 -159 2 5 0 ATÓM 1609 CB ILE 229 11.802 12.078 41.295 1.000 11:52 Anisa 1609 CB ILE 229 1257 1473 1648 34 -57 3 6 2 ATÓM 1610 CG2 ILE 229 11.997 12.852 39.999 1.000 11:30 Anisa 1610 CG2 ILE 229 1655 1211 1426 83 -189 156 ATÓM 1611 CGL ILE 229 10.575 11.131 41.237 1.000 14:39 Anisa 1611 CGL ILE 229 1031 2034 2402 -40 210 311 ATÓM 1612 CD1 ILE 229 10.676 10.093 40.138 1.000 19:20 Anisa 1612 CD1 ILE 229 2085 1723 3489 -610 93 - 13 8 ATÓM 1613 C ILE 229 14.389 12.034 41.477 1.000 10:38 Anisa 1613 C ILE 229 1293 1405 1247 -62 -169 322 ATÓM 1614 0 ILE 229 14.952 11.947 40.369 1.000 11.66 Anisa 1614 0 ILE 229 1805 1257 1368 -13 145 328 ATÓM 1615 N ALA 230 14.965 12.692 42.490 1.000 i 10.66 Anisa 1615 N ALA 230 1476 1274 1300 -104 -151 356 ATÓM 1616 CA ALA 230 16.312 13.259 42.338 1.000 1 11.21 Anisa 1616 CA ALA 230 1473 976 1813 -57 -308 9 0 ATÓM 1617 CB ALA 230 16.681 14.148 43.509 1,000 10.5 8

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-143- Anisa 1617 CB ALA 230 1350 1295 1375 62 -106 126 ATÓM 1618 C ALA 230 17.336 12.136 42132 1.000 Jrl. 2 8 Anisa 1618 C ALA 230 1640 1037 1610 1 55242 ATÓM 1619 0 ALA 230 18.220 12.185 41.273 1.000 1 1.2 9 Anisa 1619 0 ALA 230 1510 1240 1539 -189 -40 2 9 8 ATÓM 1620 N THR 231 17.173 11.097 42.946 1,000 1 0.5 5 Anisa 1620 N THR 231 1328 895 1787 -262 -70 214 ATÓM 1621 CA THR 231 18.064 9939 42.819 1,000 1 1.9 8 Anisa 1621 C A THR 231 1929 1018 1605 -164 15 9 ATÓM 1622 CB THR 231 17.717 8865 43.878 1.000 10.7 6 Anisa 1622 CB THR 231 1381 1070 1636 -86 -453 ATÓM 1623 OG1 THR 231 17.658 9437 45.198 1.000 11. 8 2 Anisa 1623 OG1 THR 231 1615 1236 1641 35 -115 277 ATÓM 1624 CG2 THR 231 18765 7752 43.880 1,000 1 2 .5 7 Anisa 1624 CG2 THR 231 1621 1314 1840 -89 3 5 1 ATÓM 1625 C THR 231 17.958 9352 41.415 1.000 12.52 Anisa 1625 C THR 231 1632 1500 1624 -144 42 1 1 ATÓM 1626 0 THR 231 18.939 9.050 40.732 1.000 12.15 Anisa 1626 0 THR 231 1636 1233 1747 -17 87 2 2 4 ATÓM 1627 N LEU 232 16.717 9.154 40.959 1.000 11.14 Anisa 1627 N LEU 232 1608 1005 1620 -68 1 4 1 ATÓM 1628 CA LEU 232 16.446 8522 39.675 1,000 1 2.47 Anisa 1628 CA LEU 232 1880 1203 1657 109 -168 4 5 ATÓM 1629 CB LEU 232 14.950 8.214 39.552 1.000 12. 81 Anisa 1629 CB LEU 232 1989 1225 1654 -78 -209 ATÓM 1630 CG LEU 232 14.452 7464 38.314 1.000 14.85 Anisa 1630 CG LEU 232 2171 1753 1719 -5 -410-9 6 ATÓM 1631 CD1 LEU 232 15.020 6.055 38.240 1.000 16.78 Anisa 1631 CD1 LEU 232 2693 1749 1932 72 -432 - 4 8 7 ATÓM 1632 CD2 LEU 232 12.914 7411 38.291 1.000 15.70 Anisa 1632 CD2 LEU 232 2180 1866 1920 -278 (589) 4 9 4 ATÓM 1633 C LEU 232 16.964 9354 38.511 1.000 11.58 Anisa 1633 C LEU 232 1452 1390 1559 309 -300 1 3 6 ATÓM 1634 0 LEU 232 17.752 8837 37.686 1,000 13.4 5 Anisa 1634 0 LEU 232 1808 1436 1867 320 -17 0 0 ATÓM 1635 N VAL 233 16.565 10.617 38.414 1.000 10. 95 Anisa 1635 N VAL 233 1428 1210 1522 -14 -210 0 ATÓM 1636 CA VAL 233 16.948 11.421 37.242 1.000 11.70 Anisa 1636 CA VAL 233 1703 1345 1397 96 5 1 3 ATÓM 1637 CB VAL 233 16.156 12.743 37.215 1.000 11.14 Anisa 1637 CB VAL 233 1672 1272 1287 -27 276 7 3 ATÓM 1638 CG1 VAL 233 16.661 13.774 38.249 1,000 13.3 4 Anisa 1638 CG1 VAL 233 1834 1562 1673 -205 653 3 6 8 ATÓM 1639 CG2 VAL 233 16.106 13.412 35.827 1.000 14.6 6 Anisa 1639 CG2 VAL 233 1992 1873 1704th -4 -45 5 8 6 ATÓM 1640 C VAL 233 18.459 11.586 37.132 1,000 13.4 1 Anisa 1640 C VAL 233 1712 1573 1811 92 151 1 2 5. ATÓM 1641 0 VAL 233 19.012 11.627 36.C21 1,000 13.4 5 Anisa 1641 0 VAL 233 1844 1402 1866 45 192 4 3 8 ATÓM 1642 N THR 234 19.188 11.665 38.250 1.000 13.13 Anisa 1642 N THR 234 1457 1639 1893 -138 223 1 2 6 ATÓM 1643 CA THR 234 20.613 11.930 38.244 1.000 13.00 Anisa 1643 CA THR 234 1483 1600 1855 -188 428 ATÓM 1644 CB THR 234 21.069 12.726 39.465 1.000 12.4 6 Anisa 1644 CB THR 234 1300 1632 1803 -32,200 2 5 1 ATÓM 1645 OG1 THR 234 20.825 11.941 40.639 1.000 13.7 1 Anisa 1645 OG1 THR 234 1660 1662 1888 191 202 2 9 1 ATÓM 1646 CG2 THR 234 20.301 14.027 39.643 1.000 1 1.3 7 Anisa 1646 CG2 THR 234 1097 1565 1657 -153 -87 ATÓM 1647 C THR 234 21.424 10.643 38.178 1,000 1 4.44 Anisa 1647 C THR 234 1550 1823 2114 6 -73-5 5 3

SUBSTTTUTE SHEET (RULE 26)

WO 99Z33994

PCT / G B98 / 03860

- 144 -

ATÓM 1648 0 THR 234 22659 10.710 38.233 1,000 1 5. 8 1 Anisa 1648 0 THR 234 1546 2169 2292 61 27-2.1 7 ATÓM 1649 N GLY 235 20.767 9.477 38.070 1.000 14.76 Anisa 1649 N GLY 235 1776 1576 2254 -77 4 10 ATÓM 1650 C A GLY 235 21.530 8249 37.994 1.000 16.69 Anisa 1650 CA GLY 235 2053 1803 2486 304 34 1 8 9 ATÓM 1651 C GLY 235 22.243 7862 39.275 1.000 16.83 Anisa 1651 C GLY 235 1854 2031 2512 765 244 193 ATÓM 1652 0 GLY 235 23.305 7.237 39.194 1.000 19.67 Anisa 1652 0 GLY 235 2074 2172 3225 1035 383 372 ATÓM 1653 N GLY 236 21.665 8.227 40.425 1.000 14:46 Anisa 1653 N GLY 236 1732 1327 2433 154 199 7 5 ATÓM 1654 CA GLY 236 22.187 7.768 41.692 1.000 15.73 Anisa 1654 CA GLY 236 2060 1381 2535 41 186 3 12 ATÓM 1655 C GLY 236 23.166 8.691 42.388 1.000 14.76 Anisa 1655 C GLY 236 1931 1332 2346 252 74 2 8 8 ATÓM 1656 0 GLY 236 23.778 8.244 43.373 1.000 18:32 Anisa 1656 0 GLY 236 1983 2197 2782 106 -105 8 4 5 ATÓM 1657 N GLN 237 23.318 9938 41/953 1.000 13.99 Anisa 1657 N GLN 237 1831 1349 2137 158 165 170 ATÓM 1658 CA GLN 237 24209 10.956 42.485 1.000 13:13 Anisa 1658 CA GLN 237 1474 1304 2210 367 -31 276 ATÓM 1659 CB GLN 237 24.629 11.948 41.383 1.000 13:38 Anisa 1659 CB GLN 237 1367 1566 2152 99 72 15 9 ATÓM 1660 CG GLN 237 25.390 11.335 40.219 1.000 14.74 Anisa 1660 CG GLN 237 1404 1529 2666 518 410 333 ATÓM 1661 CD GLN 237 25.816 12.428 39.257 1.000 17:22 Anisa 1661 CD GLN 237 2039 2018 2486 -64 426 360 ATÓM 1662 OE1 GLN 237 26.754 13.208 39.522 1.000 20.60 Anisa 1662 OE1 GLN 237 1566 2334 3928 -10 -29 9 6 6 ATÓM 1663 NE2 GLN 237 25.116 12.470 38.127 1.000 17:47 Anisa 1663 NE2 GLN 237 2014 2093 2533 208 438 408 ATÓM 1664 C GLN 237 23.627 11,739 43.663 1.000 12.90 Anisa 1664 C GLN 237 1474 1324 2105 72 -10 2 5 5 ATÓM 1665 0 GLN 237 24.332 12.549 44.282 1.000 15.90 Anisa 1665 0 GLN 237 1739 1888 2413 -291 74 - 8 4 ATÓM 1666 N VAL 238 22365 11.481 44.013 1.000 12:13 Anisa 1666 N VAL 238 1372 961 2276 212 -33 2 0 0 ATÓM 1667 CA VAL 238 21.664 12.182 45.082 1.000 11.91 Anisa 1667 CA VAL 238 1169 1436 1920 -121 -276 - 9 ATÓM 1668 CB VAL 238 20.622 13.158 44.510 1.000 12:00 Anisa 1668 CB VAL 238 1024 1179 2357 -6 199 - 2 1 ATÓM 1669 CG1 VAL 238 19.978 13.999 45.601 1.000 7.13 Anisa 1669 CG1 VAL 238 1530 1668 1766 63 -232 - 2 2 2 ATÓM 1670 CG2 VAL 238 21.207 14.088 43.463 1.000 14:00 Anisa 1670 CG2 VAL 238 1795 1470 2053 -40 -2,181 ATÓM 1671 C VAL 238 20.990 11.156 46.000 1.000 13.62 Anisa 1671 C VAL 238 1707 1415 2054 -103 -40 - 2 ATÓM 1672 0 VAL 238 20.252 10.288 45.492 1.000 12.64 Anisa 1672 0 VAL 238 1702 977 2123 60 -318 2 5 7 ATÓM 1673 N LYS 239 21.247 11.246 47.300 1.000 11.99 Anisa 1673 N LYS 239 1075 1404 2076 127 -101 7 4 ATÓM 1674 CA LYS 239 20568 10.444 48.322 1.000 12.77 Anisa 1674 CA LYS 239 1224 1541 2088 -12 -125 8 6 ATÓM 1675 CB LYS 239 21.382 10.463 49.622 1.000 i 12.23 Anisa 1675 CB LYS 239 1333 1155 2158 183 -234 - 2 7 ATÓM 1676 CG LYS 239 20.953 9.626 50.793 l.OOC l13.85 Anisa 1676 CG LYS 239 1643 1689 1931 187 -52 - 8 9 ATÓM 1677 CD LYS 239 21.927 9.579 51.957 l.OOC l 20.13 Anisa 1677 CD LYS 239 2893 1795 2960 10 -1185 5 8 8 ATÓM 1678 CE LYS 239 21.364 8745 53.098 1,000 24.73

SUBSTIT SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-145- Anisa 1678 CE LYS 239 4065 2250 3080 -348 -1466 1 0 6 4 ATÓM 1679 NZ LYS 239 22019 8841 54.420 1.000 K2-, 2 8 Anisa 1679 NZ LYS 239 5658 4315 2293 1610 - 930 - 3 0 4 ATÓM 1680 C LYS 239 19.169 10.949 48.661 1,000 1 1.59 Anisa 1680 C LYS 239 1207 1332 1866 -35 -82 6 ATÓM 1681 ABOUT LYS 239 18.976 12.191 48.708 1.00012.32 Anisa 1681 ABOUT LYS 239 1638 1294 1749 -2 -25 236 ATÓM 1682 N ALA 240 18.222 10.047 48.863 1.000 10.65 Anisa 1682 N ALA 240 1248 1266 1534 -52 -185-8 8 ATÓM 1683 CA ALA 240 16.884 10.368 49 .354 1.000 10.21 Anisa 1683 CA ALA 240 1292 1,057 1531 -195 -37 - 1 0 0 9 ATÓM 1684 CB ALA 240 15.784 9782 48.466 1.00013.46 Anisa 1684 CB ALA 240 1195 2378 1543 -232 20-4 4 3 ATÓM 1685 C ALA 240 16.784 9881 50.807 1.000 10.97 Anisa 1685 C ALA 240 1308 1249 1611 -127 -142 4 9 ATÓM 1686 ABOUT ALA 240 16.595 8.664 51.059 1.000 1 3.02 Anisa 1686 ABOUT ALA 240 2136 1242 1568 -243 28 -8 ATÓM 1687 N PRO 241 16.967 10.783 51782 1.000 11.1 3 Anisa 1687 N PRO 241 1723 1041 1466 160 -49 138 ATÓM 1688 CD PRO 241 17.172 12.237 51.654 1.000 11.17 Anisa 1688 CD PRO 241 1419 1204 1618 -180 -128 7 7 ATÓM 1689 CA PRO 241 17.043 10.340 53.166 1,000 11.9 6 Anisa 1689 CA PRO 241 1597 1447 1499 -172 -32 ATÓM 1690 CB PRO 241 17.712 11.545 53.891 1.000 14. 2 5 Anisa 1690 CB PRO 241 1875 1837 1701 -531 -383 ATÓM 1691 CG PRO 241 17.286 12.724 53.069 1.000 13. 61 Anisa 1691 CG PRO 241 2015 1446 1709 -596 -465-2 ATÓM 1692 C PRO 241 15.708 10.072 53.361 1.000 12. 3 5 Anisa 1692 C PRO 241 1417 1610 1665 -175 -188 4 1 8 ATÓM 1693 ABOUT PRO 241 14,759 10.829 53655 1.000 12. 28 Anisa 1693 ABOUT PRO 241 1359 1582 1723 -232 -468 8 1 ATÓM 1694 N ARG 242 15.700 9033 54.711 1.000 12.75 Anisa 1694 N ARG 242 1775 1407 1664 -170 75 2 5 0 ATÓM 1695 CA ARG 242 14.563 8804 55.576 1.000 10.76 Anisa 1695 CA ARG 242 1292 1417 1380 -207 -281 2 0 1 ATÓM 1696 CB ARG 242 14.614 7.405 56.223 1.000 15.02 Anisa 1696 CB ARG 242 2419 1368 1918 -358 117 2 9 4 ATÓM 1697 CG ARG 242 14.115 6.342 55.230 1,000 17 .85 Anisa 1697 CG ARG 242 3373 1274 2135 9 -560 251 ATÓM 1698 CD ARG 242 14.254 4.934 55.763 1.000 19. 42 Anisa 1698 CD ARG 242 3148 1111 3120 505 503 116 ATÓM 1699 NE ARG 242 15.667 4552 55.649 1.000 20.71 Anisa 1699 NE ARG 242 3225 2107 2536 939 638 2 1 2 ATÓM 1700 CZ ARG 242 16.107 3.444 56416 1.000 23 .22 Anisa 1700 CZ ARG 242 3198 2206 3417 307 -545 5 8 9 ATÓM 1701 NH1 ARG 242 15.285 2,567 56.980 1.000 24.46 Anisa 1701 NH1 ARG 242 4097 2112 3083 307 387 195 ATÓM 1702 NH2 ARG 242 17.416 3.184 56.438 1.000 25.4 1 Anisa 1702 NH2 ARG 242 3402 2332 3921 819 -266 4 0 3 ATÓM 1703 C ARG 242 14.477 9834 56704 1,000 11 .9 5 Anisa 1703 C ARG 242 1571 1463 1506 -248 -214 1 0 6 ATÓM 1704 ABOUT ARG 242 15.469 10.377 57.213 1,000 13.6 5 Anisa 1704 ABOUT ARG 242 1708 1439 2040 -322 -401 - 3 7 ATÓM 1705 N HIS 243 13.252 10.085 57.118 1.00011.60 Anisa 1705 N HIS 243 1657 1410 1342 -311 -206 5 ATÓM 1706 CA HIS 243 12.942 11.056 58.158 1.00011.49 Anisa 1706 CA HIS 243 1855 1571 938 -3 06 -183 1 4 0 ATÓM 1707 CB HIS 243 12.968 12.462 57.546 1.00011.22 Anisa 1707 CB HIS 243 1432 1379 1453 -231 -221 3 8 ATÓM 1708 CG HIS 243 12.133 12.694 56.341 1.00011.80 Anisa 1708 CG HIS 243 1937 1171 1378 -31 -268 7 9

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 146-

ATÓM 1709 CD2 HIS 243 10.885 13.236 56.181 1,000 11:15 Anisa 1709 CD2 HIS 243 1990 1106 1142 3 5 -341.14 1 ATÓM 1710 ND1 HIS 243 12.538 12.345 55086 1,000 12:29 Anisa 1710 ND1 HIS 243 1670 1606 1395 --394 -91 8 ATÓM 1711 CE1 HIS 243 11.599 12.653 54209 1,000 12:59 Anisa 1711 CE1 HIS 243 1686 1740 1357 -522 -202-2 2 5 3 ATÓM 1712 NE2 HIS 243 10.585 13.204 54841 1,000 10.77 Anisa 1712 ΝΞ2 HIS 243 1612 1307 1172 -616 -268 - 3 7 ATÓM 1713 C HIS 243 11,605 10.737 58.812 1,000 12:49 Anisa 1713 C HIS 243 1869 1570 1308 -321 -53 7 3 ATÓM 1714 ABOUT HIS 243 10.807 9949 58.271 1,000 12:26 Anisa 1714 ABOUT HIS 243 1756 1404 1497 -188 -114 4 7 ATÓM 1715 N HIS 244 11.352 11.319 59.983 1,000 12:16 Anisa 1715 N HIS 244 1464 1715 1442 -230 -112 - 3 2 ATÓM 1716 CA HIS 244 10.138 11.043 60758 1,000 2.12 Anisa 1716 CA HIS 244 1606 1809 1152 -599 -167-2 ATÓM 1717 CB HIS 244 10.255 9778 61615 1,000 12:51 Anisa 1717 CB HIS 244 1655 1763 1334 -19 101-4 4 ATÓM 1718 CG HIS 244 11.270 9.810 62698 1,000 4.15 Anisa 1718 CG HIS 244 2025 1723 1965 -178 -433 154 ATÓM 1719 CD2 HIS 244 11276 10.380 63923 1,000 18:19 Anisa 1719 CD2 HIS 244 2946 2339 1627 36 -732 297 ATÓM 1720 ND1 HIS 244 12.504 9.203 62.662 1,000 19:30 Anisa 1720 ND1 HIS 244 2303 2232 2800 229 -708 266 ATÓM 1721 CE1 HIS 244 13226 9.387 63731 1,000 22:48 Anisa 1721 CE1 HIS 244 2649 2734 3159 11 -1205 6 5 0 ATÓM 1722 NE2 HIS 244 12.476 10.120 64.531 1,000 22:33 Anisa 1722 NE 2 HIS 244 3088 2895 2500 -272 -1236 384 ATÓM 1723 C HIS 244 9.780 12.246 61613 1,000 13:47 Anisa 1723 C HIS 244 1897 1673 1549 -362 254 6 7 ATÓM 1724 ABOUT HIS 244 10603 13.165 61798 1,000 13:48 Anisa 1724 ABOUT HIS 244 1800 1726 1595 -283 139 -161 ATÓM 1725 N VAL 245 8.551 12.245 62130 1,000 15:26 Anisa 1725 N VAL 245 1852 1964 1983 -417 232-5 5 ATÓM 1726 CA. VAL 245 8.090 13.352 62970 1,000 17:31 Anisa 1726 CA VAL 245 2108 2442 2026 -125 476 - 1 5 1 ATÓM 1727 CB VAL 245 6939 14.169 62360 1,000 17:33 Anisa 1727 CB VAL 245 2094 2473 2019 -80 340-4 7 7 ATÓM 1728 CG1 VAL 245 6551 15.334 63286 1,000 25.25 Anisa 1728 CG1 VAL 245 2217 2966 4410 -137 1939 - 124 ATÓM 1729 CG2 VAL 245 7.252 14.713 60966 1,000 21:49 Anisa 1729 CG2 VAL 245 3070 2538 2556 -180 313 271 ATÓM 1730 C VAL 245 7682 12.768 64327 1,000 18:29 Anisa 1730 C VAL 245 2123 2689 2137 -443 508-7 1 ATÓM 1731 ABOUT VAL 245 6765 11.945 64429 1,000 18.62 Anisa 1731 ABOUT VAL 245 1810 2174 3089 -15 451 254 ATÓM 1732 N ALA 246 8.385 13.202 65369 1,000 1.54 Anisa 1732 N ALA 246 2813 3045 2327 -591 -407 9 0 7 ATÓM 1733 CA ALA 246 8.133 12.701 66719 1,000 2 5.10 Anisa 1733 CA ALA 246 4596 2562 2379 94 -225 9 9 7 ATÓM 1734 CB ALA 246 9.424 12.723 67537 1,000 29.82 Anisa 1734 CB ALA 246 5381 3408 2540 402 -888 1 3 2 5 ATÓM 1735 C ALA 246 7,080 13.545 67412 1,000 3 1.20 Anisa 1735 C ALA 246 5079 4143 2632 314 280 428 ATÓM 1736 ABOUT ALA 246 6876 14.714 67052 1,000 32.39 Anisa 1736 ABOUT ALA 246 4706 3748 3853 567 1247-6 6 ATÓM 1737 N ALA 247 6429 12.973 68413 1,000 37.30 Anisa 1737 N ALA 247 5548 5498 3126 92 640 835 ATÓM 1738 CA ALA 247 5.585 13.794 69271 1.000'4 0.4 2 Anisa 1738 CA ALA 247 5434 6048 3878 15 1313 ’850 ATÓM 1739 C ALA 247 6289 14.132 70578 1,000 2.17

SUBSTTTUIb SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-147-

Anisa 1739 C ALA 247 6495 5891 3 63 6 -823 1720 ATÓM 1740 0 ALA 247 7048 13.338 71. 136 1.000 Λ »6 3 Anisa 1740 0 ALA 247 5811 6371 3637 -1631 804 425 ATÓM 1741 CB ALA 247 4.280 13.067 69525 I. 000 7 7.1 7 Anisa 1741 CB ALA 247 5186 9059 3 67 6 -520 523 2 6 8 3 ATÓM 1742 N SER 257 1781 21,848 70382 1.000 3 1.02 Anisa 1742 N SER 257 4109 5558 2119 137 -236 - 8 1 0 ATÓM 1743 CA SER 257 1.214 21.932 69052 1,000 2 7.0 1 Anisa 1743 CA SER 257 2792 5165 2304 109 -143 - 7 0 7 ATÓM 1744 CB SER 257 0039 22.914 68992 1,000 2 8.1 6 Anisa 1744 CB SER 257 2655 4473 3572 -238 -90 - 1,070 1 ATÓM 1745 OG SER 257 0.491 24.251 69074 1.000 5 1.3 2 Anisa 1745 OG SER 257 8516 4131 6853 -616 -2734 8 8 7 ATÓM 1746 C SER 257 2,259 22.389 68034 1.000 2 6. 1 9 Anisa 1746 C SER 257 2537 5064 23 5.0 -132 -413 5 5 7 ATÓM 1747 0 SER 257 3,286 22.988 68.352 1,000 3 1.47 Anisa 1747 0 SER 257 2740 5886 3330 -435 -689 - 6 3 9 ATÓM 1748 N ARG 258 2.022 22.123 66763 1,000 2 6.04 Anisa 1748 N ARG 258 3257 4477 2151 -238 -441-1 9 ATÓM 1749 CA ARG 258 2,982  22541 65747 1.000 25. 81 Anisa 1749 CA ARG 258 2606 4735 24 66 73 -338-1 9 7 ATÓM 1750 C ARG 258 2.321 22.609 64383 1.000 18.2 6 Anisa 1750 C ARG 258 2374 2541 2021 38 83 - 8 5 4 ATÓM 1751 0 ARG 258 1.288 21.967 64131 1.000 19.2 3 Anisa 1751 0 ARG 258 2600 2819 1888 -389,311 - 4 2 0 ATÓM 1752 CB ARG 258 4188 21.592 65664 1.000 2 9. 78 Anisa 1752 CB ARG 258 3403 5052 2861 695 -552-5 5 7 ATÓM 1753 CG ARG 258 4246 20.784 64.384 1.000 32. 64 Anisa 1753 CG ARG 258 4358 4148 3896 145 97 - 5 6 1 ATÓM 1754 CD ARG 258 5325 19.746 64499 1.000 30.3 8 Anisa 1754 CD ARG 258 3812 4423 3309 -57,341 - 1,66 ATÓM 1755th NE ARG 258 6,433 19.909 63581 1.000 29. 43 Anisa 1755 NE ARG 258 3990 4604 2588 -22 71 5 4 2 ATÓM 1756 CZ ARG 258 6.453 19.389 62359 1.000 25.02 Anisa 1756 CZ ARG 258 2540 3893 3074 304 -243 1 0 4 ATÓM 1757 NH1 ARG 258 5.456 18.677 61835 1.000 22.8 8 Anisa 1757 NH1 ARG 258 2105 2607 3982 (+420) 359 315 289 ATÓM 1758 NH2 ARG 258 7523 19.593 61617 1.000 22.03 Anisa 1758 NH2 ARG 258 2477 2775 3120 -430 -287-9 6 4 ATÓM 1759 N THR 259 2927 23.415 63527 1,000 2 0.17 Anisa 1759 N THR 259 2010 3640 2013 -743 91-1001 ATÓM 1760 CA THR 259 2,485 23.505 62138 1.00018.33 Anisa 1760 CA THR 259 1801 3043 2121 -533 43 - 6 8 ATÓM 1761 CB THR 259 1,821 24.821 61713 1.000 23.23 Anisa 1761 CB THR 259 2082 3169 3576 -384 -164 - 5 8 0 0 ATÓM 1762 OG1 THR 259 2,839 25.830 61681 1.000 34.27 Anisa 1762 OG1 THR 259 2181 2562 8277 -137 -996-7 9 4 ATÓM 1763 CG2 THR 259 0738 25.198 62704 1.000 25.4 9 Anisa 1763 CG2 THR 259 4466 2233 2987 325,396 - 9 4 8 ATÓM 1764 C THR 259 3,702 23.352 61222 1,000 18.4 4 Anisa 1764 C THR 259 2035 2822 2150 - 753 274 - 5 8 3 ATÓM 1765 0 THR 259 4835 23.698 61603 1.000 24.7 4 Anisa 1765 0 THR 259 1961 5370 2069 -964 231-7 1 4 ATÓM 1766 N SER 260 3.420 22.867 60026 1.000 1 6.2 9 Anisa 1766 N SER 260 1971 2352 1864 -224 2-7 5 ATÓM 1767 CA SER 260 4447 22.832 58.989 1.000 17.43 Anisa 1767 CA SER 260 1783 2961 1879 321 -95-7 2 ATÓM 1768 CB SER 260 5224 21.514 58956 1,000 2 0.17 Anisa 1768 CB SER 260 2306 3257 2100 761 -127 3 8 8 ATÓM 1769 OG SER 260 4.416 20.392 58.698 1,000 2 7.0 9 Anisa 1769 OG SER 260 3651 2803 3839 426 217554

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 148-

ATÓM 1770 C SER 260 3832 23.062 57.614 1.000 14:52 Anisa 1770 C SER 260 1463 2165 1889 83 -lfrO - »- 1 ATÓM 1771 ABOUT SER 260 2686 22.681 57.402 1.000 15.92 Anisa 1771 ABOUT SER 260 1513 2489 2049 '-93 -12 5 7 ATÓM 1772 N SER 261 4617 23.660 56.742 1.000 13:45 Anisa 1772 N SER 261 1489 1832 1788 -190 -120-5 5 0 0 ATÓM 1773 CA SER 261 4294 23.864 55.334 1.000 13:52 Anisa 1773 CA SER 261 1599 1726 1812 -204 30 - 3 1 6 ATÓM 1774 C SER 261 5.209 22.943 54.545 1.000 12:45 Anisa 1774 C SER 261 1332 1887 1513 -42 -240-1 1 6 1 ATÓM 1775 ABOUT SER 261 6438 23.072 54.662 1.000 7.15 Anisa 1775 ABOUT SER 261 1344 1885 2497 -68 -331- 3 4 3 ATÓM 1776 CB SER 261 4.446 25.330 54.943 1.000 17.76 Anisa 1776 CB SER 261 2718 1625 2404 -399 -485- 3 1 8 ATÓM 1777 OG SER 261 4428 25.554 53.570 1.000 27.54 Anisa 1777 OG SER 261 4342 3308 2814 -719 -821 955 ATÓM 1778 N VAL 262 4623 22.045 53.782 1.000 10.90 Anisa 1778 N VAL 262 1215 1630 1298 41 -13 5 19 ATÓM 1779 CA VAL 262 5393 21.031 53.026 1.000 11.61 Anisa 1779 CA VAL 262 1334 1634 1442 156 -103 1 7 ATÓM 1780 CB VAL 262 5026 19.639 53.558 1.000 11.87 Anisa 1780 CB VAL 262 1262 1636 1613 9 -187 - 7 4 ATÓM 1781 CG1 VAL 262 5.778 18.577 52.779 1.000 13:12 Anisa 1781 CG1 VAL 262 1462 1527 1997 -2 185 5 1 ATÓM 1782 CG2 VAL 262 5.262 19.564 55.062 1.000 8.17 Anisa 1782 CG2 VAL 262 3390 1494 1604 -374 -245 3 9 ATÓM 1783 C VAL 262 5.096 21.149 51.543 1.000 11:18 Anisa 1783 C VAL 262 1026 1790 1430 1 -111 -138 ATÓM 1784 ABOUT VAL 262 3939 20.969 51.127 1.000 12.76 Anisa 1784 ABOUT VAL 262 1064 2137 1648 -251 -84 -2 7 0 ATÓM 1785 N PHE 263 6.090 21.438 50.714 1.000 9:50 Anisa 1785 N PHE 263 995 1297 1316 -6 -210 -18 1 ATÓM 1786 CA PHE 263 5.933 21.637 49.288 1.000 9.61 Anisa 1786 CA PHE 263 1310 1017 1324 -6 -284 - 4 2 ATÓM 1787 CB PHE 263 6486 23.002 48.848 1.000 10.94 Anisa 1787 CB PHE 263 1282 1055 1821 -50 -253 4 ATÓM 1788 CG PHE 263 6.150 23.399 47.418 1.000 10:35 Anisa 1788 CG PHE 263 +420 779 1231 1921 -58 32 3 4 0 ATÓM 1789 CD1 PHE 263 6858 22.915 46.326 1.000 9.98 Anisa 1789 CD1 PHE 263 765 1183 1841 -26 -101 2 4 0 ATÓM 1790 CD2 PHE 263 5106 24.277 47.148 1.000 11.95 Anisa 1790 CD2 PHE 263 1229 1261 2052 245 -29 2 5 1 ATÓM 1791 CE1 PHE 263 6.530 23.229 45.019 1.000 12:49 Anisa 1791 CE1 PHE 263 1718 1173 1856 31 -370 136 ATÓM 1792 CE2 PHE 263 4769 24.601 45.836 1.000 13:12 Anisa 1792 CE2 PHE 263 1451 1382 2151 43 -292 354 ATÓM 1793 CZ PHE 263 5491 24.112 44.762 1.000 12:42 Anisa 1793 CZ PHE 263 1318 1453 1948 -138 -186 6 4 9 ATÓM 1794 C PHE 263 6.636 20.505 48.530 1.000 8.91 Anisa 1794 C PHE 263 1076 1085 1223 -39 -142 2 4 ATÓM 1795 ABOUT PHE 263 7868 20.406 48.538 1.000 10.98 Anisa 1795 ABOUT PHE 263 1098 1233 1842 -120 -224 - 1 4 6 ATÓM 1796 N PHE 264 5856 19.691 47.812 1.000 9.19 Anisa 1796 N PHE 264 1089 1266 1136 -86 -105-8 2 ATÓM 1797 CA PHE 264 6386 18.602 46.991 1.000 9.64 Anisa 1797 CA PHE 264 1009 1238 1417 -56 -60 - 12 6 ATÓM 1798 CB PHE 264 5.483 17.358 47.005 1.000 9.92 Anisa 1798 CB PHE 264 1209 1201 1359 -78 17 9 ATÓM 1799 CG PHE 264 5.265 16.673 48.336 1.000 11:22 Anisa 1799 CG PHE 264 1241 1647 1374 -121 38 7 7 ATÓM 1800 CD1 PHE 264 6.292 16.236 49.139 1.000 i 15.38

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 149-

ANISOU 1800 CD1 PHE 264 14 67 2641 1734 -225 -8 8 7 3 ATÓM 1801 CD2 PHE 264 3. 986 16.433 48.808 1,000Jr-96 ANISOU 1801 CD2 PHE 264 1425 3252 1769 -610 -79 958 ATÓM 1802 CE1 PHE 264 6.090 15.596 53.336 1.000 14:52 ANISOU 1802 CE1 PHE 264 1745 2417 1354 162 334 452 ATÓM 1803 CE2 PHE 264 3755 15.796 50.019 1.000 4.18 ANISOU 1803 CE2 PHE 264 1747 3405 1704 -590 -109 1 0 0 7 ATÓM 1804 CZ PHE 264 4817 15.354 50.779 1.000 12:52 ANISOU 1804 CZ PHE 264 1772 1536 1449 -57 227 334 ATÓM 1805 C PHE 264 6.535 19.038 45.533 1.000 8.98 ANISOU 1805 C PHE 264 1103 918 1392 143 81 -92 ATÓM 1806 0 PHE 264 5497 19.368 44.930 1.000 9.79 ANISOU 1806 0 PHE 264 991 1190 1540 28 105 10 3 ATÓM 1807 N LEU 265 7758 19.031 44.999 1.000 8:43 ANISOU 1807 N LEU 265 992 884 1325 173 -180 1 4 8 ATÓM 1808 CA LEU 265 7984 19.224 43.566 1.000 8.66 ANISOU 1808 CA LEU 265 883 1066 1339 63 -33 -76 ATÓM 1809 CB LEU 265 9.309 19.964 43.328 1.000 10:10 ANISOU 1809 CB LEU 265 1179 1188 1469 -225 -220 248 ATÓM 1810 CG LEU 265 9.570 20.351 41.871 1.000 9:37 ANISOU 1810 CG LEU 265 1072 1009 1478 242 25129 ATÓM 1811 CD1 LEU 265 8725 21.522 41.408 1.000 10.80 ANISOU 1811 CD1 LEU 265 1291 1004 1811 181 -114 296 ATÓM 1812 CD2 LEU 265 11.048 20.684 41.678 1.000 10.87 ANISOU 1812 CD2 LEU 265 1129 1483 1519 134 42 1 4 6 ATÓM 1813 C LEU 265 7.933 17.849 42.875 1.000 10:21 ANISOU 1813 C LEU 265 932 1188 1760 -6 -38 -3 02 ATÓM 1814 0 LEU 265 8858 17.043 43.042 1.000 10:45 ANISOU 1814 0 LEU 265 1388 968 1612 84 -217 10 7 ATÓM 1815 N ARG 266 6,853 17.530 42.135 1.000 10:00 ANISOU 1815 N ARG 266 1325 1069 1404 -120 -222 1 5 ATÓM 1816 CA ARG 266 6572 16.198 41.628 1.000 10:50 ANISOU 1816 CA ARG 266 1219 1217 1554 -294 110 -210 ATÓM 1817 CB ARG 266 5208 15.675 42.124 1.000 10:56 ANISOU 1817 CB ARG 266 978 1460 1574 -168 -103 - 051 ATÓM 1818 CG ARG 266 4965 15.894 43.609 1.000 11:24 ANISOU 1818 CG ARG 266 1337 1373 1563 -40 119 206 ATÓM 1819 CD ARG 266 3668 15.318 44.146 1.000 11:17 ANISOU 1819 CD ARG 266 1113 1567 1564 -17 -49 - 1 1 ATÓM 1820 NE ARG 266 2,508 15.879 43.447 1.000 9:43 ANISOU 1820 NE ARG 266 1341 1157 1087 24 -100 - 1 4 5 ATÓM 1821 CZ ARG 266 1.236 15.509 43.657 1.000 9.83 ANISOU 1821 CZ ARG 266 1245 1194 1294 132 -159-1 ATÓM 1822 NH1 ARG 266 0.961 14.567 44.572 1.000 11:20 ANISOU 1822 NH1 ARG 266 1208 1240 1805 -144 -453 2 7 2 ATÓM 1823 NH2 ARG 266 0225 16.048 42.975 1.000 11.8 ANISOU 1823 NH2 ARG 266 1460 1265 1484 191 -284 7 3 ATÓM 1824 C ARG 266 6.601 16.190 40.099 1.000 10:28 ANISOU 1824 C ARG 266 1273 1089 1545 -200 -5 -167 ATÓM 1825 0 ARG 266 6027 17.109 39.519 1.000 11.5 ANISOU 1825 0 ARG 266 1254 1153 1793 -132 47-6 6 ATÓM 1826 N PRO 267 7,215 15.162 39.4196 1.000 10:27 ANISOU 1826 N PRO 267 1194 1239 1468 -33 130 3 2 ATÓM 1827 CD PRO 267 7828 13.963 40.109 1.000 i 12.36 ANISOU 1827 CD PRO 267 1865 1132 1697 -26 -529-1 9 2 ATÓM 1828 CA PRO 267 7304 15.157 38.036 1.000 * 10:12 ANISOU 1828 CA PRO 267 1278 1095 1472 -129 38 - 18 5 ATÓM 1829 CB PRO 267 8,250 13.986 37.767 1,000 11.83 ANISOU 1829 CB PRO 267 1489 1088 1919 -72 91 - 3 2 2 ATÓM 1830 CG PRO 267 8017 13.053 38.913 1,000 1 0.72 ANISOU 1830 CG PRO 267 960 1356 1755 95 -257 - 1 7 8

SUBSTmiTE SHEET (RULE 25)

WO 99/33994

PCT / GB98 / 03860

- 150-

ATÓM 1831 C PRO 267 5977 14.929 37.344 1,000 1 0.8 6 Anisa 1831 C PRO 267 1330 1226 1570 -252- 16 1 ATÓM 1832 0 PRO 267 5.030 14.421 37.934 1.000 1 2.03 Anisa 1832 0 PRO 267 1316 1174 2080 -258 17 7 7 ATÓM 1833 N ASN 268 5931 15.288 36.065 1.000 10.61 Anisa 1833 N ASN 268 1216 1146 1670 - 70 - 86 - 1 2 9 ATÓM 1834 C A ASN 268 4.810 14.949 35.198 1.000 1 1.2 0 Anisa 1834 CA ASN 268 1285 1349 1622 -167 -43 2 9 ATÓM 1835 CB ASN 268 4954 15.664 33846 1.000 14.02 Anisa 1835 CB ASN 268 2160 1410 1756 132 -315 2 3 ATÓM 1836 CG ASN 268 4,992 17.175 33.992 1.000 13.03 Anisa 1836 CG ASN 268 1811 1393 1747 189 -355-8 8 ATÓM 1837 OD1 ASN 268 4.046 17.748 34.566 1.00016.65 Anisa 1837 OD1 ASN 268 1910 1744 2673 292 -1-1 5 9 ATÓM 1838 ND2 ASN 268 6037 17.818 33.495 1.00014.19 Anisa 1838 ND2 ASN 268 2505 1372 1516 161 264-1 7 2 ATÓM 1839 C ASN 268 4,705 13.446 34.968 1.00010.88 Anisa 1839 C ASN 268 1294 1314 1526 -75 -226 - ATÓM 1840 0 ASN 268 5.715 12.732 34.979 1.000 11.68 Anisa 1840 0 ASN 268 1534 1439 1464 87 -458-1 1 2 1 ATÓM 1841 N ALA 269 3,484 12.980 34.688 1.00012.22 Anisa 1841 N ALA 269 1484 1428 1732 -108 -397 4 4 7 ATÓM 1842 CA ALA 269 3.277 11.547 34417 1.00012.12 Anisa 1842 CA ALA 269 1432 1356 1819 -238 -29-2 8 2 ATÓM 1843 CB ALA 269 1,817 11.310 34.058 1.00012.38 Anisa 1843 CB ALA 269 1439 1278 1985 -228 -183 2 9 ATÓM 1844 C ALA 269 4.125 10.981 33.283 1.000 11.26 Anisa 1844 C ALA 269 1445 1240 1592 25 -280 -1 4 1 ATÓM 1845 0 ALA 269 4493 9,800 33.263 1.00012.53 Anisa 1845 0 ALA 269 1428 1249 2085 -110 108 -18 7 ATÓM 1846 N ASP 270 4438 11.799 32276 1.00011.47 Anisa 1846 N ASP 270 1701 1280 1378 -261 -341 - 3 0 0 ATÓM 1847 CA ASP 270 5.214 11.378 31.113 1.00011.92 Anisa 1847 CA ASP 270 1826 1106 1595 19 -183 - 1 5 7 ATÓM 1848 CB ASP 270 4.760 12.096 29.850 1.00014.13 Anisa 1848 CB ASP 270 1733 2038 1597 83 111 2 12 ATÓM 1849 CG ASP 270 5,050 13.568 29.777 1.00015.98 Anisa 1849 CG ASP 270 2309 1939 1823 416 -418 5 6 4 ATÓM 1850 OD1 ASP 270 5432 14.186 30.762 1.000 21.61 Anisa 1850 OD1 ASP 270 4101 1797 2312 176 -515 16 3 ATÓM 1851 OD2 ASP 270 4.880 14.152 28.674 1.000 24.64 Anisa 1851 OD2 ASP 270 3995 3221 2145 -62 -168 1 3 9 5 ATÓM 1852 C ASP 270 6721 11.542 31264 1.000 12. 8 6 Anisa 1852 C ASP 270 1840 1392 1654 -398 -61 3 1 6 ATÓM 1853 0 ASP 270 7.443 11.290 30292 1.000 14.83 Anisa 1853 0 ASP 270 1813 2114 1709 -346 -141 ATÓM 1854 N PHE 271 7.230 11.911 32439 1.000 11. 85 Anisa 1854 N PHE 271 1360 1316 1824 60 -25 7 0 ATÓM 1855 CA PHE 271 8665 11.927 32.715 1.000 11.14 Anisa 1855 CA PHE 271 1242 1349 1641 10,230 1 6 2 ATÓM 1856 CB PHE 271 8972 12.378 34.143 1.000 12.19 Anisa 1856 CB PHE 271 1467 1444 1722 -96 -3182 ATÓM 1857 CG PHE 271 10.385 11.992 34.597 1.000 12.77 Anisa 1857 CG PHE 271 1411 1640 1800 43 31 5 6 ATÓM 1858 CD1 PHE 271 11.475 12.488 33904 1.000 13.22 Anisa 1858 CD1 PHE 271 1513 1516 1993 168,220 4 9 ATÓM 1859 CD2 PHE 271 10.624 11.155 35.666 1.000 13.55 Anisa 1859 CD2 PHE 271 1343 1674 2131 138 84 2 5 5 ATÓM 1860 CE1 PKE 271 12.779 12.178 34.249 1.000 14.26 Anisa 1860 CE1 PHE 271 1432 1760 2225 -39 46- 4 1 6 ATÓM 1861 CE2 PHE 271 11.925 10.806 36.019 1.000 15.88

SUBSTffiE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 151 -

Anisa 1861 CE2 PHE 271 1537 1818 26 7 9 -263 -675 260 ATÓM 1862 CZ PHE 271 13.006 11.288 35.304 1,000 1-4.15 Anisa 1862 CZ PHE 271 1166 1736 2 <> 6 5 7 -530 - 4 6 7 ATÓM 1863 C PHE 271 9.259 10.550 32.410 1,000 11:27 Anisa 1863 C PHE 271 1359 1338 1Ξ85 75,271 3 4 8 ATÓM 1864 0 PHE 271 8785 9531 32.920 1,000 12.97 Anisa 1864 0 PHE 271 2011 1320 1596 -85 473 279 ATÓM 1865 N THR 272 10.261 10.498 31.541 1,000 11.95 Anisa 1865 N THR 272 1018 1503 2020 -214 300-1 1 5 ATÓM 1866 CA THR 272 10.823 9254 30.992 1,000 12.70 Anisa 1866 CA THR 272 1615 1557 1652 132 341 146 ATÓM 1867 CB THR 272 10.679 9.281 29.450 1,000 16.79 Anisa 1867 CB THR 272 1814 2829 1737 -595 157 - 4 0 7 ATÓM 1868 OGL THR 272 9.301 9471 29.090 1,000 2.18 Anisa 1868 OG1 THR 272 1912 2921 20L3 -497 -73 9 1 ATÓM 1869 CG2 THR 272 11.200 7.976 28.856 1,000 2.17 Anisa 1869 CG2 THR 272 2144 2857 1467 -475 538-1 9 4 ATÓM 1870 C THR 272 12.272 9.057 31.423 1,000 2.12 Anisa 1870 C THR 272 1436 1573 1559 92 603 i 1 3 7 ATÓM 1871 0 THR 272 13.055 10.031 31437 1,000 14:17 Anisa 1871 0 THR 272 1451 1583 2351 125 602 412 ATÓM 1872 N PHE 273 12.625 7837 31.828 1,000 12:34 Anisa 1872 N PHE 273 1402 1585 17G3 17 378 158 ATÓM 1873 CA PHE 273 13.953 7.492 32312 1,000 12:20 Anisa 1873 CA PHE 273 1362 1364 1909 -126 336 147 ATÓM 1874 CB PHE 273 13.951 7.514 33861 1,000 12:37 Anisa 1874 CB PHE 273 1362 1447 1890 -102 211-8 ATÓM 1875 CG PHE 273 12.988 6.528 34.491 1,000 11.65 Anisa 1875 CG PHE 273 1398 1631 1396 -367 42 -2 15 ATÓM 1876 CD1 PHE 273 11.684 6.889 34.773 1,000 14:11 Anisa 1876 CD1 PHE 273 1531 2214 1614 -336 293-6 6 ATÓM 1877 CD2 PHE 273 13.409 5.245 34.803 1,000 13:20 Anisa 1877 CD2 PHE 273 2024 1639 1352 -358 339-9 ATÓM 1878 CE1 PHE 273 10.793 5993 35.323 1,000 13:25 Anisa 1878 CE1 PHE 273 1536 2081 1418 -98 447 4 2 ATÓM 1879 CE2 PHE 273 12.530 4329 35.327 1,000 13:39 Anisa 1879 CE2 PHE 273 1529 1905 1654 -224 140 283 ATÓM 1880 CZ PHE 273 11.227 4,706 35.604 1,000 14.75 Anisa 1880 CZ PHE 273 1444 2260 1902 -90 -187 2 7 5 ATÓM 1881 C PHE 273 14.423 6135 31.795 1,000 12:45 Anisa 1881 C PHE 273 1278 1526 1927 -120 317-3 3 ATÓM 1882 0 PHE 273 13.645 5311 31.291 1,000 11.95 Anisa 1882 0 PHE 273 1590 1580 1370 -137 226-1 ATÓM 1883 N SER 274 15.717 5854 31.952 1,000 7.12 Anisa 1883 N SER 274 1270 1640 1677 -29 559 3 5 3 ATÓM 1884 CA SER 274 16.335 4.586 31.604 1,000 14:39 Anisa 1884 CA SER 274 1583 1534 2349 43 707 384 ATÓM 1885 CB SER 274 17.845 4771 31.438 1,000 14:49 Anisa 1885 CB SER 274 1578 1727 2202 213 695 329 ATÓM 1886 OG SER 274 18.564 3.558 31.424 1,000 14.97 Anisa 1886 OG SER 274 1763 1848 2078 349 348-13 ATÓM 1887 C SER 274 16.100 3,505 32.666 1,000 13:12 Anisa 1887 C SER 274 1670 1481 1833 8,461 1 3 7 ATÓM 1888 0 SER 274 16.438 3,700 33.834 1,000 13:50 Anisa 1888 0 SER 274 1493 1518 2116 -65 119 1 5 ATÓM 1889 N VAL 275 15.533 2,359 32.271 1,000 11.90 Anisa 1889 N VAL 275 1476 1618 1427 -110 490 195 ATÓM 1890 CA VAL 275 15.283 1,254 33.180 1,000 11:41 Anisa 1890 CA VAL 275 1708 1424 1204 -8,286 7 6 ATÓM 1891 CB VAL 275 14.346 0198 32.543 1,000 12.74 Anisa 1891 CB VAL 275 1732 1300 1809 63 164 - 1 6

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-152-

ATÓM 1892 CG1 VAL 275 14.157 -1,020 33.437 1,000 1 6.1 0 Anisa 1892 CG1 VAL 275 2352 1803 1962 -614 -I & 3 3 7 0 ATÓM 1893 CG2 VAL 275 12.961 0763 32.261 1.000 13.81 Anisa 1893 CG2 VAL 275 1535 1786 1924 16 363 126 ATÓM 1894 C VAL 275 16.577 0622 33.692 1.000 12.62 Anisa 1894 C VAL 275 1574 1628 1594 14 375 136 ATÓM 1895 0 VAL 275 16.729 0405 34.926 1,000 1 3.0 1 Anisa 1895 0 VAL 275 1667 1643 1634 9 119 1 8 0 ATÓM 1896 N PRO 276 17.569 0286 32.889 1.000 14.64 Anisa 1896 N PRO 276 1583 2066 1914 2,454 - 4 2 ATÓM 1897 CD PRO 276 17.583 0.285 31.415 1.000 15.84 Anisa 1897 CD PRO 276 1565 2536 1916 89,755 3 5 ATÓM 1898 CA PRO 276 18.827 -0,250 33.453 1.00016.76 Anisa 1898 CA PRO 276 1667 2403 2296 261 391 - 1 6 3 ATÓM 1899 CB PRO 276 19.732 -0.503 32.236 1.00018.27 Anisa 1899 CB PRO 276 1804 2568 2571 411 573 - 1 4 2 ATÓM 1900 CG PRO 276 18.868 -0,385 31.029 1.000 18.9 6 Anisa 1900 CG PRO 276 2147 2763 2293 724 694 - 3 7 ATÓM 1901 C PRO 276 19.500 0.710 34.420 1.00016.32 Anisa 1901 C PRO 276 1521 2342 2336 116 237 6 7 ATÓM 1902 0 PRO 276 20.035 0.277 35.456 1.00016.78 Anisa 1902 0 PRO 276 1411 2689 2275 93,376 2 5 3 ATÓM 1903 N LEU 277 19.475 2.019 34.155 1.000 16.58 Anisa 1903 N LEU 277 1835 2412 2052 -15,483 1 4 8 ATÓM 1904 CA LEU 277 20.142 2,919 35.099 1.000 17.70 Anisa 1904 CA LEU 277 1990 2226 2511 -21,362 1 1 8 ATÓM 1905 CB LEU 277 20.298 4277 34.425 1.000 20.20 Anisa 1905 CB LEU 277 2952 2292 2432 -1 -14 2 7 0 ATÓM 1906 CG LEU 277 21.048 5.359 35.186 1.000 20.86 Anisa 1906 CG LEU 277 2213 2221 3490 -32 -354 4 8 2 ATÓM 1907 CD1 LEU 277 22.446 4888 35531 1.000 34.24 Anisa 1907th CD1 LEU 277 2157 2303 8.552 69 -842 258 ATÓM 1908 CD2 LEU 277 21.062 6.620 34.334 1.000 31.91 Anisa 1908 CD2 LEU 277 4745 2460 4918 -476 -572 1 1 5 0 ATÓM 1909 C LEU 277 19.411 2.989 36.430 1.000 16.55 Anisa 1909 C LEU 277 1975 1885 2430 -218 211 -2 4 3 ATÓM 1910 0 LEU 277 19.997 3.116 37.517 1.000 19.19 Anisa 1910 0 LEU 277 2179 2636 2476 -616 50 1 2 2 ATÓM 1911 N ALA 278 18.080 2.905 36.386 1.00015.48 Anisa 1911 N ALA 278 2008 1904 1969 -357 279 1 1 2 ATÓM 1912 CA ALA 278 17.308 2896 37.636 1.000 14. 5 1 Anisa 1912 CA ALA 278 2109 1763 1641 -308 74 1 6 7 ATÓM 1913 CB ALA 278 15.814 2896 37.347 1.000 15.41 Anisa 1913 CB ALA 278 2017 1773 2064 66 302 6 2 6 ATÓM 1914 C ALA 278 17.710 1,684 38.479 1.00014.55 Anisa 1914 C ALA 278 1972 1869 1689 -195 -257 7 9 ATÓM 1915 0 ALA 278 17.894 1.770 39.683 1.000 13. 80 Anisa 1915 0 ALA 278 1444 2144 1655 -250 -166 9 9 ATÓM 1916 N ARG 279 17.841 0.530 37.842 1.000 13.86 Anisa 1916 N ARG 279 1795 1728 1742 -432 -128 1 6 0 9 ATÓM 1917 CA ARG 279 18.242 -0,679 38.560 1,000 15.8 8 Anisa 1917 CA ARG 279 1995 1973 2064 59,355 4 1 1 ATÓM 1918 CB ARG 279 18.204 -1,922 37.648 1.00016.83 Anisa 1918 CB ARG 279 1889 1897 2609 84,544,250 ATÓM 1919 CG ARG 279 16.790 -2,323 37291 1.000 19. 63 Anisa 1919 CG ARG 279 2123 2196 3139 -63,233 9 1 ATÓM 1920 CD ARG 279 16.656 -3,288 36131 1.000 27.03 Anisa 1920 CD ARG 279 3924 3198 3150 -603 -275 -1 9 8 ATÓM 1921 NE ARG 279 17.236 -4,578 36.364 1,000 27.4 5 Anisa 1921 NE ARG 279 4659 2854 2915 -359 751 - 7 8 9 ATÓM 1922 CZ ARG 279 16.714 -5,717 36.779 1.000 32.8 5

suBSTmrre sheet (rule 25)

WO 99/33994

PCT / GB98 / 03860

-153-

Anisa 1922 CZ ARG 279 4486 3045 4948 -475 44S-2 2 2 ATÓM 1923 NH1 ARG 279 15.424 -5,874 37089 1,000 «6» Anisa 1923 NH1 ARG 279 4653 2168 4 562 -103 968 - 6 7 8 ATÓM 1924 NH2 ARG 279 17.551 -6,750 3ó .890 1,000 7.87 Anisa 1924 NH2 ARG 279 4879 2436 7074 -276 3278 - 8 ATÓM 1925 C ARG 279 19.628 -0,519 39.150 1,000 17:48 Anisa 1925 C ARG 279 2118 1653 2871 75 -8 7 0 5 ATÓM 1926 0 ARG 279 19.916 -1,064 40.212 1,000 6.82 Anisa 1926 0 ARG 279 3764 3102 3 325 -1987 -1466 1 3 8 ATÓM 1927 N GLU 280 20.538 0189 38.505 1,000 17.73 Anisa 1927 N GLU 280 1983 2293 2459 109 609 3 7 ATÓM 1928 CA GLU 280 21.899 0317 3S.026 1,000 19.66 Anisa 1928 CA GLU 280 2049 2023 3396 125 215 737 ATÓM 1929 CB GLU 280 22.836 0886 37.936 1,000 2 0.17 Anisa 1929 CB GLU 280 1648 2457 3560 464 140 1 0 9 9 ATÓM 1930 CG GLU 280 22.964 -0,149 36818 1,000 3 1.79 Anisa 1930 CG GLU 280 3477 4175 4427 801 1187-4 ATÓM 1931 CD GLU 280 23.698 0341 35.590 1,000 9.66 Anisa 1931 CD GLU 280 5144 5703 4221 -64 1339-6 ATÓM 1932 OE1 GLU 280 24.466 1.327 35.685 1,000 9.65 Anisa 1932 OEL GLU 280 3464 5891 5710 334 573 1 6 3 9 ATÓM 1933 OE2 GLU 280 23.489 -0,294 34.519 1,000 41.55 Anisa 1933 OE2 GLU 280 5257 6747 37B1 2245 -183 10 2 ATÓM 1934 C GLU 280 21.984 1,188 40.266 1,000 19.68 Anisa 1934 C GLU 280 1488 2350 3640 -566 161 4 9 0 ATÓM 1935 0 GLU 280 23.031 1.142 40.958 1,000 25.69 Anisa 1935 0 GLU 280 1871 3766 4123 231 -245 1 8 0 ATÓM 1936 N CYS 281 20.943 1.980 40.565 1,000 18:57 Anisa 1936 N CYS 281 1560 2609 2887 -406 -212 17 6 ATÓM 1937 CA CYS 281 21.098 2.762 41.806 1,000 23.83 Anisa 1937 CA CYS 281 3222 2647 3184 -1,189 176 -12 2 ATÓM 1938, CB CYS 281 21.079 4264 41.523 1,000 2 5.40 Anisa 1938 CB CYS 281 3278 2655 3718 -426 368-4 6 ATÓM 1939 SG CYS 281 19.587 4904 40.763 1,000 27.05 Anisa 1939 SG CYS 281 3069 2914 4295 -522 -37-7 9 4 ATÓM 1940 C CYS 281 20.098 2.406 42.907 1,000 16.99 Anisa 1940 C CYS 281 1377 1604 3475 109 -6 - 5 4 7 ATÓM 1941 0 CYS 281 19.971 3,173 43.889 1,000 4.17 Anisa 1941 0 CYS 281 2294 1277 29C2 -204 -483 - 1 2 9 ATÓM 1942 N GLY 282 19.447 1.245 42.794 1,000 15:23 Anisa 1942 N GLY 282 1617 1597 2572 3 -58 - 4 3 7 ATÓM 1943 CA GLY 282 18.731 0674 43.914 1,000 15.61 Anisa 1943 CA GLY 282 1565 1973 2394 6 -331-2 6 6 ATÓM 1944 C GLY 282 17.246 0519 43.727 1,000 13.75 Anisa 1944 C GLY 282 1635 1562 2029 -270 -446-7 8 ATÓM 1945 0 GLY 282 16.585 0.012 44.639 1,000 14.99 Anisa 1945 0 GLY 282 1751 1630 2313 207 -242 455 ATÓM 1946 N PHE 283 16.744 1.009 42582 1,000 12.65 Anisa 1946 N PHE 283 1434 1803 1570 -200 18 - 2 6 2 ATÓM 1947 CA PHE 283 15.292 0886 42374 1,000 11.80 Anisa 1947 CA PHE 283 1477 1032 1974 -15 -264 4 6 ATÓM 1948 CB PHE 283 14.839 1,890 41.295 1,000 14:13 Anisa 1948 CB PHE 283 2262 971 2136 109 -187 1 5 9 ATÓM 1949 CG PHE 283 14.906 3.351 41.757 1,000 12.63 Anisa 1949 CG PHE 283 1711 1033 205.5 47 -86 9 ATÓM 1950 CDI PHE 283 13.851 3928 42.409 1,000 13:45 Anisa 1950 CDI PHE 283 1697 1399 2 013 -166 24 - 2 ATÓM 1951 CD2 PHE 283 16.037 4.111 41.519 1,000 13:15 Anisa 1951 CD2 PHE 283 1567 1135 2295 142 -41- 9 9 ATÓM 1952 CE1 PHE 283 13.903 5.248 42.839 1,000 15.61 Anisa 1952 CE1 PHE 283 2111 1649 2171 -202 484-6 6 7

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 154 -

ATÓM 1953 CE2 PHE 283 16.112 5432 41963 1,000 12.60 Anisa 1953 CE2 PHE 283 1783 936 2068 32 -18 - ATÓM 1954 CZ PHE 283 15.040 5993 42.641 1,000 13:37 Anisa 1954 CZ PHE 283 1863 865 2352 187-1 -149 1 3 ATÓM 1955 C PHE 283 14.915 -0,534 41.972 1,000 11:23 Anisa 1955 C PHE 283 1527 975 1765 63 -172 6 5 ATÓM 1956 ABOUT PHE 283 15.471 -1,071 40.990 1,000 13:24 Anisa 1956 ABOUT PHE 283 1249 1428 2355 175 -120 3 6 1 ATÓM 1957 N ASP 284 13.998 -1,130 42.712 1,000 12:31 Anisa 1957 N ASP 284 1607 1333 1736 -268 -312 8 7 ATÓM 1958 CA ASP 284 13589 -2,528 42.527 1,000 12:48 Anisa 1958 CA ASP 284 1725 1202 1814 -148 -543 350 ATÓM 1959 CB ASP 284 13.159 -3,156 43876 1,000 12.67 Anisa 1959 CB ASP 284 2014 1145 1656 -50 -405 1 3 5 ATÓM 1960 CG ASP 284 13.261 -4,667 43.909 1,000 13:40 Anisa 1960 CG ASP 284 2077 1171 1843 110 -419 363 ATÓM 1961 OD1 ASP 284 13.861 -5,246 42.974 1,000 14.98 Anisa 1961 OD1 ASP 284 1956 1094 2640 -87 11 6 0 ATÓM 1962 OD2 ASP 284 12.762 -5,306 44.883 1,000 15.79 Anisa 1962 OD2 ASP 284 2494 1539 1966 -330 -446 438 ATÓM 1963 C ASP 284 12.478 -2,641 41.510 1,000 10.82 Anisa 1963 C ASP 284 1238 1387 1487 -205 -99 123 ATÓM 1964 ABOUT ASP 284 11.373 -3,100 41.777 1,000 12:28 Anisa 1964 ABOUT ASP 284 1331 1175 2159 -209 48191 ATÓM 1965 N VAL 285 12.751 -2,154 40.308 1,000 11:32 Anisa 1965 N VAL 285 1204 1671 1,426 -93 -48 6 1 ATÓM 1966 CA VAL 285 11.748 -2,062 39.260 1,000 11:45 Anisa 1966 CA VAL 285 1468 1384 1500 39 -219-1 ATÓM 1967 CB VAL 285 12.153 -1,072 38157 1,000 11:58 Anisa 1967 CB VAL 285 1412 1523 1465 -388 -428-8 ATÓM 1968 CG1 VAL 285 12.278 0362 38.679 1,000 2.15 Anisa 1968 CG1 VAL 285 2209 1458 2040 -264 -442- 3 2 ATÓM 1969 CG2 VAL 285 13.467 -1,482 37495 1,000 15.70 Anisa 1969 CG2 VAL 285 1909 1443 2615 -159 308 4 4 7 ATÓM 1970 C VAL 285 11.424 -3,431 38.642 1,000 10.83 Anisa 1970 C VAL 285 1232 1281 1602 93 -220 1 0 8 ATÓM 1971 ABOUT VAL 285 12.267 -4,301 38.520 1,000 12:13 Anisa 1971 0 VAL 285 1214 1192 2202 -28 300 1 5 2 ATÓM 1972 N SER 286 10.168 -3,523 38.248 1,000 11.9 Anisa 1972 N SER 286 1116 1608 1489 -76 96 7 ATÓM 1973 CA SER 286 9.558 -4,622 37.510 1,000 11:32 Anisa 1973 CA SER 286 1104 1479 1718 -41 -274 2 5 2 ATÓM 1974 CB SER 286 8.483 -5,292 38.344 1,000 9.88 Anisa 1974 CB SER 286 1328 1141 1285 72 -207 7 0 ATÓM 1975 OG SER 286 7,570 -4,361 38.905 1,000 11:34 Anisa 1975 OG SER 286 1391 1188 1729 147 -156 7 5 ATÓM 1976 C SER 286 9.019 -4,106 36.175 1,000 10:34 Anisa 1976 C SER 286 1127 1227 1575 -87 2 4 5 ATÓM 1977 ABOUT SER 266 7829 -4,112 35.869 1,000 12.62 Anisa 1977 ABOUT SER 286 1223 2219 1353 0 -178 228 ATÓM 1978 N LEU 287 9926 -3,622 35.335 1,000 12:45 Anisa 1978 N LEU 287 1414 1664 1653 -212 3 16 1 ATÓM 1979 CA LEU 287 9.654 -2,900 34.099 1,000 12:59 Anisa 1979 CA LEU 287 1622 1558 1605 -366 93 1 8 4 ATÓM 1980 CB LEU 287 10.145 -1,452 34.210 1,000 12.91 Anisa 1980 CB LEU 287 1716 1591 1597 -373 -95 2 7 ATÓM 1981 CG LEU 287 9452 -0,590 35.264 1,000 12.96 Anisa 1981 CG LEU 287 1182 1848 1895 -407 -51 -17 0 ATÓM 1982 CD1 LEU 287 10.229 0.708 35.484 1-000 13:34 Anisa 1982 CD1 LEU 287 1644 1108 2318 -38 -124 223 ATÓM 1983 CD2 LEU 287 8006 -0,248 34.914 1,000 14:56

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-155 -

aniscu 1983 CD2 LEU 287 1716 1548 2267 36 -550 318 ATÓM 1984 C LEU 287 10.319 -3,610 32928 1.000Λ2 ,. 6 3 Anisa 1984 C LEU 287 1837 1244 1719 -233 248 3 5 4 ATÓM 1985 0 LEU 287 11.529 -3,805 32.916 -1.000 16.6 8 Anisa 1985 0 LEU 287 1779 1998 2560 -292 390-1 4 9 ATÓM 1986 N ASP 288 9531 -4,045 31.950 1.000 13.91 Anisa 1986 N ASP 288 2080 1751 1455 4,223 2 2 7 ATÓM 1987 C A ASP 288 10.079 -4,688 30759 1.000 15.50 Anisa 1987 C Ä ASP 288 2029 2269 1593 -122,605 1 5 3 ATÓM 1988 CB ASP 288 8.979 -5,478 30.043 1.000 17.00 Anisa 1988 CB ASP 288 2722 2125 1613 -250 362-2 ATÓM 1989 CG ASP 288 9.480 -6,452 29.014 1.000 19.30 Anisa 1989 CG ASP 288 2467 2980 1885 172 243 - 3 7 7 ATÓM 1990 ODL ASP 288 10.447 -7,183 29.292 1,000 2 5.9 5 Anisa 1990 ODL ASP 288 2812 3190 3856 501 -239-7 8 3 ATÓM 1991 OD 2 ASP 288 8911 -6,508 27907 1,000 3 1.7 6 Anisa 1991 OD2 ASP 288 5375 4430 2260 1266 - 849 - 1 1 5 4 ATÓM 1992 C ASP 288 10.654 -3,652 29.811 1.000 17.08 Anisa 1992 C ASP 288 2259 2631 1602 -262 248 5 3 4 ATÓM 1993 0 ASP 288 10.197 -2,502 29.708 1.000 23.31 Anisa 1993 0 ASP 288 4276 2268 2313 -244 -13 2 9 7 ATÓM 1994 N GLY 289 11.702 -3,966 29.049 1.000 21.2 6 Anisa 1994 N GLY 289 2748 3699 1632 -610 752 5 0 1 ATÓM 1995 CA GLY 289 12.116 -2,880 28.152 1.000 21.65 Anisa 1995 CA GLY 289 2842 3988 1396 -1162 71 6 2 6 ATÓM 1996 C GLY 289 13.084 -1,859 28.736 1.000 22.09 Anisa 1996 C GLY 289 2888 3509 1996 -738 -23 2 3 4 ATÓM 1997 0 GLY 289 13.414 -1,836 29.924 1.000 20.34 Anisa 1997 0 GLY 289 3230 2606 1891 -917 124 14 7 ATÓM 1998 N GLU 290 13.562 -0,952 27.869 1.000 16.48 Anisa 1998 N GLU 290 2665 2099 1496 5 222-44 5 ATÓM 1999 CA GLU 290 14.716 -0,117 28.182 1.00016.94 Anisa 1999 ' CA GLU 290 2470 2161 1806 81,411 - 4 8 4 ATÓM 2000 CB GLU 290 15.579 0.012 26.912 1.000 20.2 6 Anisa 2000 CB GLU 290 2670 2740 2287 414 862 - 2 3 9 ATÓM 2001 CG GLU 290 16.071 -1,333 26.386 1.000 24.53 Anisa 2001 CG GLU 290 3251 3153 2916 663 1218 - 6 1 2 ATÓM 2002 CD GLU 290 16.812 -2,170 27.411 1.000 27.91 Anisa 2002 CD GLU 290 3019 3161 4424 989,940 - 2 5 1 ATÓM 2003 OE1 GLU 290 17.874 -1,747 27.917 1.000 35.13 Anisa 2003 OE1 GLU 290 3913 4458 4975 963 -85-8 7 7 ATÓM 2004 OE2 GLU 290 16.336 -3,280 27.734 1.000 43.76 Anisa 2004 OE2 GLU 290 6893 3257 6478 -30 -749 5 9 8 ATÓM 2005 C GLU 290 14.406 1,271 28716 1.00014.67 Anisa 2005 C GLU 290 2512 1756 1308 95,142 1 0 ATÓM 2006 0 GLU 290 15.260 1.840 29.412 1.000 15.25 Anisa 2006 0 GLU 290 2074 1969 1750 50,418 - 2 6 2 ATÓM 2007 N THR 291 13.232 1.814 28.437 1.00015.72 Anisa 2007 N THR 291 2173 2393 1406 78,346 - 5 1 9 ATÓM 2008 CA THR 291 12.792 3087 28.991 1.000 15.16 Anisa 2008 CA THR 291 2080 1845 1833 -88 631-1 ATÓM 2009 CB THR 291 12.766 4,226 27.956 1.000 18.67 Anisa 2009 CB THR 291 2724 2529 1842 -361 769 ATÓM 2010 OG1 THR 291 11.756 4009 26.976 1.000 22.93 Anisa 2010 OG1 THR 291 3313 3135 2265 447 78 1 4 6 ATÓM 2011 CG2 THR 291 14.096 4.306 27213 1,000 2 1.82 Anisa 2011 CG2 THR 291 3035 2126 313 357 1449 9 0 2 ATÓM 2012 C THR 291 11.402 2.920 29.622 1.000 12.86 Anisa 2012 C THR 291 1863 1604 1421 47 305 219 ATÓM 2013 0 THR 291 10.625 2,024 29.270 1.000 16.13 Anisa 2013 0 THR 291 2344 1983 1804 -303 750 4 4 1

SUBSTITUTE SHEET (RULE 26)

PCT / GB98 / 03860

- 156 -

WO 99/33994 ATÓM 2014 N ALA 292 11.037 Anisa 2014 N ALA 292 1495 ATÓM 2015 CA ALA 292 9.746 Anisa 2015 CA ALA 292 1362 ATÓM 2016 CB ALA 292 9718 Anisa 2016 CB ALA 292 1768 ATÓM 2017 C ALA 292 9.385 Anisa 2017 C ALA 292 1317 ATÓM 2018 0 ALA 292 10266 Anisa 2018 0 ALA 292 1389 ATÓM 2019 N THR 293 8091 Anisa 2019 N THR 293 1486 ATÓM 2020 CA THR 293 7626 Anisa 2020 CA THR 293 1717 ATÓM 2021 CB THR 293 6.352 Anisa 2021 CB THR 293 2128 ATÓM 2022 OG1 THR 293 5317 Anisa 2022 OG1 THR 293 1831 ATÓM 2023 CG2 THR 293 6474 Anisa 2023 CG2 THR 293 1791 ATÓM 2024 C THR 293 7.363 Anisa 2024 C THR 293 1439 ATÓM 2025 0 THR 293 7.211 Anisa 2025 0 THR 293 1049 ATÓM 2026 N PHE 294 7.243 Anisa 2026 N PHE 294 1794 ATÓM 2027 CA PHE 294 6.806 f r Anisa 2027 CA PHE 294 1432 ATÓM 2028 CB PHE 294 6709 - Anisa 2028 CB PHE 294 1930 ATÓM 2029 CG PHE 294 6.270 Anisa 2029 CG PHE 294 1880 ATÓM 2030 CD1 PHE 294 7123 Anisa 2030 CD1 PHE 294 1976 ATÓM 2031 CD2 PHE 294 4989 Anisa 2031 CD2 PHE 294 2180 ATÓM 2032 CE1 PHE 294 6726 Anisa 2032 CE1 PHE 294 1598 ATÓM 2033 CE2 PHE 294 4575 Anisa 2033 CE2 PHE 294 2214 ATÓM 2034 CZ PHE 294 5426 Anisa 2034 CZ PHE 294 2040 ATÓM 2035 C PHE 294 5484 Anisa 2035 C PHE 294 1401 ATÓM 2036 0 PHE 294 5325 Anisa 2036 0 PHE 294 1396 ATÓM 2037 N GLN 295 4487 Anisa 2037 N GLN 295 1399 ATÓM 2038 CA GLN 295 3,217 Anisa 2038 CA GLN 295 1433 ATÓM 2039 CB GLN 295 2.284 Anisa 2039 CB GLN 295 1425 ATÓM 2040 CG GLN 295 0.951 Anisa 2040 CG GLN 295 1573 ATÓM 2041 CD GLN 295 0052 Anisa 2041 CD GLN 295 1592 ATÓM 2042 OE1 GLN 295 0.349 Anisa 2042 OE1 GLN 295 2306 ATÓM 2043 NE2 GLN 295 -1,053 Anisa 2043 NE2 GLN 295 1511 ATÓM 2044 C GLN 295 3412

3791 30.542 1,000 12:41 1363 1859 -2 256-1. .7 3839 31.202 1,000 11:57 1257 1779 -213 153 3 7 2.954 32439 1,000 12.62 1245 1784 100 357 4 5.255 31.614 1,000 10:32 1335 1270 -181 99 5 4 6.134 31.701 1,000 10.97 • 1138 1641 -146 279 104 5445 31.882 1,000 12:32 1547 1647 -314 562 - 2 8 4 • 6715 32.421 1,000 12:28 1460 1489 -168 337 - 2 0 1 7,215 31.733 1,000 13:27 1182 1730 -258 -159-2 8 4 6237 31911 1,000 13.85 1217 2216 8 -131 7 5 7303 30.212 1,000 13.72 1683 1738 -252 -56 -4 0 6 6635 33937 1,000 10:58 1050 1533 12 447 '9 5.576 34553 1,000 10:29 1102 1758 -56 93118 7.810 34569 1,000 11:53 1093 1494 -307 306-6 6 7939 35.950 1,000 10:41 1061 1463 -174 125 -162 9426 36.336 1,000 12:25 1030 1694 -164 292-6 4 9.658 37.770 1,000 12.77 1136 1837 -103 177 - 4 2 7 9462 38,839 1,000 14.73 1893 1727 -539 161 -13 2 10.068 38.056 1,000 16:59 1923- 2199 348 386-4 9 2 9.673 40144 1,000 14:36 2028 1830 -505 280-1 1 8 10.275 39.345 1,000 16.75 2062 2087 692 144 - 5 0 2 10.065 40.413 1,000 15:17 1,426 2296 327 97 - 13 5 7195 36.172 1,000 10.89 1200 1536 -155 78137 6.425 37.125 1,000 10.67 1297 1360 90,337 1 0 5 7355 35.299 1,000 10.62 1187 1450 -18 88-24 6.612 35.393 1,000 11:31 1205 1660 -96 120 - 3 1 2 7053 34254 1,000 11.66 1053 1953 -25 63 - 1 3 1 6.360 34.200 1,000 11.5 1011 1614 -93 -118 1 8 6.843 33087 1,000 11:35 1326 1395 173 57-13 7.823 32.378 1,000 6.15 1589 18 2.5 - · 110 7 3 7 8 6153 32914 1,000 13.90 1757 2015 156 -282 208 5.107 35.389 1,000 10:12

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 157 -

Anisa 2044 C GLN 295 1154 1203 1486 21 160-1 19 1 ATÓM 2045 ABOUT GLN 295 2.827 4309 36.128 1.000 ja. 8 2 Anisa 2045 ABOUT GLN 295 1264 1542 1586 -107 4113 7 ATÓM 2046 N ASP 296 4267 4558 34538 1,000 9:35 Anisa 2046 N ASP 296 1076 1056 1422 -118 -76 - 2 7 4 ATÓM 2047 CA ASP 296 4,655 3.172 34416 1,000 9.91 Anisa 2047 CA ASP 296 1241 1139 1387 56 60 -243 ATÓM 2048 CB ASP 296 5.699 2.852 33347 1,000 10:26 Anisa 2048 CB ASP 296 1315 1156 1429 113 132 - 3 7 ATÓM 2049 CG ASP 296 5343 2,981 31.885 1,000 11:42 Anisa 2049 CG ASP 296 1357 1578 1405 358 121-19 9 ATÓM 2050 ODL ASP 296 4.143 2.904 31.531 1,000 13.82 Anisa 2050 ODL ASP 296 1511 1744 1997 149 -209-6 6 2 ATÓM 2051 OD2 ASP 296 6282 3.151 31047 1,000 13:48 Anisa 2051 OD2 ASP 296 1802 1758 1564 228 366 7 3 ATÓM 2052 C ASP 296 5.175 2,682 35.770 1,000 10:31 Anisa 2052 C ASP 2 9 6 1416 1141 1361 16 91 -19 8 ATÓM 2053 ABOUT ASP 296 4852 1.551 36.197 1,000 11:40 Anisa 2053 ABOUT ASP 296 1428 1452 1453 -288 32 3 5 ATÓM 2054 N TRP 297 6004 3,484 36.441 1,000 10.88 Anisa 2054 N TRP 297 1752 1144 1238 -161 11 5 5 ATÓM 2055 CA TRP 297 6.646 3.104 37.685 1,000 11:26 Anisa 2055 CA TRP 297 1768 1215 1294 -217 -57 4 5 ATÓM 2056 CB TRP 297 7.899 3.999 37.890 1,000 10:31 Anisa 2056 CB TRP 297 1387 1417 1112 -87 213 12 0 ATÓM 2057 CG TRP 297 8.621 3651 39.172 1,000 10.98 Anisa 2057 CG TRP 297 1456 1394 132 4 164 -29 - 4 3 ATÓM 2058 CD2 TRP 297 9.082 4534 40.202 1,000 12:49 Anisa 2058 CD2 TRP 297 1255 1729 1761 75 -298-197 ATÓM 2059 CE2 TRP 297 9,692 3755 41.201 1,000 8.16 Anisa 2059 CE2 TRP 297 1860 2049 2202 -294 -978 4 9 ATÓM 2060 CE3 TRP 297 9.040 5.910 40.379 1,000 17:41 Anisa 2060 CE3 TRP 297 2778 1740 2096 -388 -916 - 2 3 4 ATÓM 2061 CD1 TRP 297 8.969 2,400 39589 1,000 13:58 Anisa 2061 CD1 TRP 297 1617 1518 2025 0 -664 114 ATÓM 2062 NE1 TRP 297 9614 2.444 40.808 1,000 16:12 Anisa 2062 NE1 TRP 297 2165 1909 2051 -22 -873 220 ATÓM 2063 CZ2 TRP 297 10.243 4.320 42.341 1,000 19.85 Anisa 2063 CZ2 TRP 297 2756 2383 2,404 -951 -1337 267 ATÓM 2064 GB3 TRP 297 9.586 6466 41.515 1,000 23:40 Anisa 2064 GB3 TRP 297 4215 2030 2645 -1001 -1758 - 7 7 ATÓM 2065 CH2 TRP 297 10.181 5.670 42486 1,000 21:51 Anisa 2065 CH2 TRP 297 3178 2457 2537 -910 -1473 -51 ATÓM 2066 C TRP 297 5,700 3.138 38.882 1,000 10:39 Anisa 2066 C TRP 297 1172 1448 1329 -280 -237 391 ATÓM 2067 ABOUT TRP 297 5.574 2.159 39639 1,000 13:52 Anisa 2067 ABOUT TRP 297 1748 1830 1557 32 -91 7 0 4 ATÓM 2068 N ILE 298 5033 4,272 39079 1,000 8.12 Anisa 2068 N ILE 298 1400 1710 148C -49 82 4 5 1 ATÓM 2069 CA ILE 298 4.223 4.521 40272 1,000 13:43 Anisa 2069 CA ILE 298 1301 2484 1317 -199 -158-3 3 ATÓM 2070 CB ILE 298 4.370 5.988 40689 1,000 16.97 Anisa 2070 CB ILE 298 1877 2908 1661 -1000 214 -630 ATÓM 2071 CG2 ILE 298 3.538 6423 41876 1,000 2 2.01 Anisa 2071 CG2 ILE 298 3980 3121 1263 -233 547 - 3 3 9 ATÓM 2072 CGL ILE 298 5847 6.253 41.037 1,000 27.10 Anisa 2072 CGL ILE 298 2588 5151 2557 -2140 -709 9 7 ATÓM 2073 CD1 ILE 298 6.365 5.522 42.266 1,000 4 3.13 Anisa 2073 CD1 ILE 298 5185 8299 2904 -3717 -3055 708 ATÓM 2074 C ILE 298 2,772 4.116 40.131 1,000 10.94 Anisa 2074 C ILE 298 1350 1652 1156 -165 -78 9 6

SUBSTTTUIt SHEET (RULE 26)

WO 99/33994

PCT / CB98 / 03860

- 158-

ATÓM 2075 0 ILE 298 2.137 3844 41155 1,000 12.67 Anisa 2075 0 ILE 298 1689 1634 1493 -102 12, 3 5 2 ATÓM 2076 N GLY 299 2.267 4.077 38.897 1,000 10:14 Anisa 2076 N GLY 299 1412 1057 1384 -51 -377 201 ATÓM 2077 CA GLY 299 0.866 3,822 38.695 1,000 10.72 Anisa 2077 CA GLY 299 1335 1084 1655 -229 - 2 0 6 ATÓM 2078 C GLY 299 0049 5054 38.369 1,000 5.12 Anisa 2078 C GLY 299 1422 1293 1864 105 -292 0 ATÓM 2079 0 GLY 299 0.585 6.088 37.976 1,000 13:11 Anisa 2079 0 GLY 299 1917 1199 1866 174 80-23 ATÓM 2080 N GLY 300 -1,268 4931 38.490 1,000 13.92 Anisa 2080 N GLY 300 1393 1531 2363 182 -410 - 2 ATÓM 2081 C A GLY 300 -2,237 5.932 38.087 1,000 2.14 Anisa 2081 CA GLY 300 1524 1471 2331 217 -563 - 3 ATÓM 2082 C GLY 300 -2,587 7.015 39074 1,000 11.97 Anisa 2082 C GLY 300 940 1603 2004 67 -488 -295 ATÓM 2083 0 GLY 300 -3,322 7.950 38.722 1,000 10.90 Anisa 2083 0 GLY 300 1219 1408 1515 -37 -203-1 ATÓM 2084 N ASN 301 -2,090 6.910 40.285 1,000 11.64 Anisa 2084 N ASN 301 947 1557 19 -383 -327 1 6 5 ATÓM 2085 CA ASN 301 -2,195 7915 41.323 1,000 13:39 Anisa 2085 CA ASN 301 1626 1904 1557 -191 -403 183 ATÓM 2086 CB ASN 301 -3,047 7.301 42.427 1,000 17.60 Anisa 2086 CB ASN 301 1391 2869 2426 -9 326 i 2 2 8 ATÓM 2087 CG ASN 301 -4,021 8196 43.108 1,000 19:15 Anisa 2087 CG ASN 301 2549 2827 1900 805 58 3 7 7 ATÓM 2088 OD1 ASN 301 -5,072 8.606 42.591 1,000 15:47 Anisa 2088 OD1 ASN 301 1258 2340 2280 -253 339-8 ATÓM 2089 ND2 ASN 301 -3,661 8.510 44.367 1,000 29.28 Anisa 2089 ND2 ASN 301 3585 4783 2758 1521 -850 - 8 8 5 ATÓM 2090 C ASN 301 -0,862 8.331 41914 1,000 11:31 Anisa 2090 C ASN 301 1436 1669 1194 1 1 -16 8 ATÓM 2091 0 ASN 301 -0,033 7,456 42.221 1,000 3.12 Anisa 2091 0 ASN 301 1483 1548 1542 -151 -279 8 2 ATÓM 2092 N TYR 302 -0,634 9628 42133 1,000 11:53 Anisa 2092 N TYR 302 1186 1584 1611 -61 26 1 0 2 ATÓM 2093 CA TYR 302 0573 10.046 42.838 1,000 11.90 Anisa 2093 CA TYR 302 1260 1395 1865 5 -211 2 2 5 ATÓM 2094 CB TYR 302 0.657 11.589 43.036 1,000 13:14 Anisa 2094 CB TYR 302 1768 1404 1820 -273 190 181 ATÓM 2095 CG TYR 302 1,082 12.287 41.750 1,000 10.88 Anisa 2095 CG TYR 302 1395 1347 1393 -321 2 -153 ATÓM 2096 CD1 TYR 302 2,421 12.439 41.413 1,000 11:29 Anisa 2096 CD1 TYR 302 1385 1246 1659 -58 98-46 ATÓM 2097 CE1 TYR 302 2859 13.075 40248 1,000 10.60 Anisa 2097 CE1 TYR 302 1055 1241 1732 -11 52-1 ATÓM 2098 CD2 TYR 302 0161 12.793 40.858 1,000 11:30 Anisa 2098 CD2 TYR 302 1304 1332 1656 -145 105 - 2 7 ATÓM 2099 CE2 TYR 302 0573 13.406 39.690 1,000 11.72 Anisa 2099 CE2 TYR 302 1013 1733 1708 -288 -138 161 ATÓM 2100 CZ TYR 302 1.907 13.551 39.375 1,000 10:35 Anisa 2100 CZ TYR 302 1009 1214 1709 -229 -50-1 9 ATÓM 2101 OH TYR 302 2.284 14.153 38.202 1,000 11.82 Anisa 2101 OH TYR 302 1192 1532 1766 -8 103 10 4 ATÓM 2102 C TYR 302 0654 9349 44.196 1,000 12:45 Anisa 2102 C TYR 302 1517 1450 1765 -181 -202 2 1 7 ATÓM 2103 0 TYR 302 -0.375 9.230 44.878 1,000 13:55 Anisa 2103 0 TYR 302 1464 1925 1759 -339 -211 7 ATÓM 2104 N VAL 303 1.868 8.967 44.542 1,000 1 2: 0 7 Anisa 2104 N VAL 303 1517 1653 1413 -135 -3 3 4 0 ATÓM 2105 CA VAL 303 2.309 8,430 45.820 1,000 11.88

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

-159-

Anisa 2105 CA VAL 303 1434 1609 1471 -368 -197 223 ATÓM 2106 CB VAL 303 2.755 6.967 45.736 1,000 Tue, - _t 5 7 Anisa 2106 CB VAL 303 1395 1682 24 59 -217 -913 312 ATÓM 2107 CG1 VAL 303 3.131 6462 47.132 1. 000 17:33 Anisa 2107 CG1 VAL 303 2644 1608 2331 -48 -1115 6 1 ATÓM 2108 CG2 VAL 303 1.703 6041 45.122 1,000 14.80 Anisa 2108 CG2 VAL 303 1876 1676 2069 -592 -639 322 ATÓM 2109 C VAL 303 3.467 9.328 46.303 1,000 13.88 Anisa 2109 C VAL 303,870 1791 26 13 75 -286 -375 ATÓM 2110 ABOUT VAL 303 4.526 9417 45.681 1,000 19.70 Anisa 2110 ABOUT VAL 303 1064 2307 4114 -61 323-9 9 9 ATÓM 2111 N ASN 304 3.271 10.046 47.393 1,000 13.77 Anisa 2111 N ASN 304 1681 1815 1737 -479 -388 140 ATÓM 2112 CA ASN 304 4.205 11.077 47.828 1,000 13:37 Anisa 2112 CA ASN 304 1626 1240 2212 -213 -533 279 ATÓM 2113 CB ASN 304 3.460 12.223 48.566 1,000 13:24 Anisa 2113 CB ASN 304 1206 1454 2370 -243 -344 296 ATÓM 2114 CG ASN 304 2.457 12.922 47.667 1,000 14:16 Anisa 2114 CG ASN 304 1142 2326 1910 146 -88 230 ATÓM 2115 OD1 ASN 304 2.776 13.283 46.540 1,000 16.65 Anisa 2115 OD1 ASN 304 1408 2456 2464 107 185 916 ATÓM 2116 ND2 ASN 304 1.263 13.126 48.209 1,000 17:45 Anisa 2116 ND2 ASN 304 1414 2961 2257 545 181 315 ATÓM 2117 C ASN 304 5.325 10.588 48.728 1,000 11:18 Anisa 2117 C ASN 304 1382 1299 1566 -183 -163 112 ATÓM 2118 ABOUT ASN 304 6.396 11.232 48.699 1,000 7.12 Anisa 2118 ABOUT ASN 304 1325 1382 1879 -167 -66 - 5 9 ATÓM 2119 N ILE 305 5.092 9.541 49.516 1,000 12:56 Anisa 2119 N ILE 305 1791 1296 1685 -152 -232 2 0 2 ATÓM 2120 CA ILE 305 6.063 9.011 50.4.63 1,000 1.14 Anisa 2120 CA ILE 305 2314 1393 1614 -55 -478 7 9 ATÓM 2121 CB ILE 305 5.781 9.493 51.906 1,000 14:44 Anisa 2121 CB ILE 305 2223 1604 1659 -29 -217 157 ATÓM 2122 CG2 ILE 305 5.725 11.017 51.956 1,000 15:31 Anisa 2122 CG2 ILE 305 1768 1608 2441 43 -479-3 3 14 ATÓM 2123 CG1 ILE 305 4.543 8.853 52.498 1,000 14.83 Anisa 2123 CG1 ILE 305 1779 1694 2163 27 -307-1 1,533 ATÓM 2124 CD1 ILE 305 4.163 9252 53.900 1,000 28.68 Anisa 2124 CD1 ILE 305 3788 5324 1786 -1,491 381 9 2 ATÓM 2125 C ILE 305 6.059 7.487 50.389 1,000 12.79 Anisa 2125 C ILE 305 1703 1355 1800 -260 -586 231 ATÓM 2126 ABOUT ILE 305 5.111 6.864 49.897 1,000 15.63 Anisa 2126 ABOUT ILE 305 1779 1564 2597 -185 -1008 2 7 6 ATÓM 2127 N ARG 306 7.170 6896 50.829 1,000 4.13 Anisa 2127 N ARG 306 1618 1389 1946 -368 -598 383 ATÓM 2128 • CA ARG 306 7.340 5435 50.868 1,000 11.82 Anisa 2128 CA ARG 306 1352 1366 1773 -375 -154 444 ATÓM 2129 CB ARG 306 8.111 4965 49.640 1,000 15:28 Anisa 2129 CB ARG 306 1976 1941 1886 -368 -19 111 ATÓM 2130 CG ARG 306 8.203 3472 49.395 1,000 17:16 Anisa 2130 CG ARG 306 2566 1953 2001 -68 -68 7 6 ATÓM 2131 CD ARG 306 8.344 3,075 47.937 1,000 19:51 Anisa 2131 CD ARG 306 2921 2361 2130 -397 -396 - 3 0 2 ATÓM 2132 NE ARG 306 7.078 3,198 47.212 1,000 20.65 Anisa 2132 NE ARG 306 2693 2844 2309 -1056 -310 214 ATÓM 2133 CZ ARG 306 6.948 3186 45.893 1,000 17:11 Anisa 2133 CZ ARG 306 2006 2225 2268 45 -91,596 ATÓM 2134 NH1 ARG 306 8.013 3.065 45.083 1,000 121.58 Anisa 2134 NH1 ARG 306 2405 2677 3116 -232 381-6 6 9 ATÓM 2135 NH2 ARG 306 5.734 3301 45365 1,000 117.51 Anisa 2135 NH2 ARG 306 2235 1550 2868 150 -484-1

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 160-

ATÓM 2136 C ARG 306 8035 5.027 52.155 1.000 1 3.4 5 Anisa 2136 C ARG 306 2254 1018 1837 -247 jr481 9 8 ATÓM 2137 0 ARG 306 9006 5.682 52.556 1,000 12 *. 1 5 Anisa 2137 0 ARG 306 1902 1099 1615 -18 -362-8 0 ATÓM 2138 N ARG 307 7571 3,968 52.811 1.000 18.19 Anisa 2138 N ARG 307 3073 1620 2218 -734 -938 7 9 2 ATÓM 2139 CA ARG 307 8.197 3.380 53.989 1.000 19.2 0 Anisa 2139 CA ARG 307 3053 1963 2277 -675 -1236 6 3 4 ATÓM 2140 C ARG 307 9086 2,191 53.611 1,000 2 3.08 Anisa 2140 C ARG 307 4018 1905 2847 -270 -1885 329 ATÓM 2141 0 ARG 307 8636 1.292 52.895 1,000 3 5. 93 Anisa 2141 0 ARG 307 6003 2403 5244 38 -3227-7 9 1 ATÓM 2142 CB ARG 307 7131 2918 54.997 1,000 2 8.2 5 Anisa 2142 CB ARG 307 5557 3297 1882 -1503 -277 509 ATÓM 2143 CG ARG 307 6.032 3921 55.275 1,000 3 3.3 9 Anisa 2143 CG ARG 307 4564 4859 3261 -1613 731 208 ATÓM 2144 CD ARG 307 5022 3.523 56.317 1.000 40.42 Anisa 2144 CD ARG 307 6335 5701 3322 -1900 1263 971 ATÓM 2145 NE ARG 307 5.605 2.952 57.529 1.000 50.83 Anisa 2145 NE ARG 307 8119 7287 3908 -2786 105 1 6 2 4 ATÓM 2146 CZ ARG 307 4.894 2.441 58.530 1.000 5 1.3 6 Anisa 2146 CZ ARG 307 7424 8064 4025 -3650 -966 ATÓM 2147 NH1 ARG 307 3567 2.422 58.485 1.000 69.51 Anisa 2147 NH1 ARG 307 7586 10951 7874 -6970 -2008 3 2 4 5 ATÓM 2148 NH2 ARG 307 5489 1937 59.600 1.000 59.99 Anisa 2148 NH2 ARG 307 10714 8150 3930 -5,986 -3291 2 0 2 8 ATÓM 2149 N THR 308 10.347 2147 54.048 1.000 22.92 Anisa 2149 N THR 308 2759 2587 3364 -589 -200 1 0 0 ATÓM 2150 CA THR 308 11.215 1.009 53.794 1.000 24.47 Anisa 2150 CA THR 308 3382 2649 3268 -360 51 1 5 0 ATÓM 2151 C THR 308 10.602 -0,252 54.382 1.000 31.10 Anisa 2151 C THR 308 5251 2520 4044 -767 16 2 7 9 ATÓM 2152 0 THR 308 10.610 -1,292 53.718 1.000 31. 44 Anisa 2152 0 THR 308 4573 2676 4696 -457 -1745 - 3 0 ATÓM 2153 CB THR 308 12.615 1,279 54.378 1.000 23.51 Anisa 2153 CB THR 308 3718 2086 3131 416 -694 5 4 2 ATÓM 2154 OG1 THR 308 13.195 2.410 53705 1.000 23.61 Anisa 2154 OG1 THR 308 2711 2503 3754 153 437-9 ATÓM 2155 CG2 THR 308 13.573 0141 54117 1,000 2 6.3 7 Anisa 2155 CG2 THR 308 4427 2796 2796 927 -329-1.8 ATÓM 2156 N SER 309 10.066 -0,156 55.596 1.000 28.39 Anisa 2156 N SER 309 3759 2774 4252 -19 2 1 3 0 1 ATÓM 2157 CA SER 309 9.488 -1,335 56.238 1.000 34.69 Anisa 2157 CA SER 309 6110 3146 3925 -1066 -1089 ATÓM 2158 C SER 309 8.109 -1,737 55.724 1.000 41.41 Anisa 2158 C SER 309 6442 3910 5383 -2171 -1170 2 1 4 4 ATÓM 2159 0 SER 309 7672 -2,884 55952 1.000 57.05 Anisa 2159 0 SER 309 11389 5141 5146 -4907 -2077 2 0 2 6 ATÓM 2160 CB SER 309 9.450 -1,104 57.755 1,000 3 1.6 1 Anisa 2160 CB SER 309 4863 2958 4188 -483 369 9 6 2 ATÓM 2161 OG SER 309 8.485 -0,135 S8.107 1.000 38.99 Anisa 2161 OG SER 309 4731 3477 6604 313 -2249 - 4 9 6 ATÓM 2162 N LYS 310 7.391 -0,868 55.032 1.000 47.69 Anisa 2162 N LYS 310 5502 5577 7040 -539 -1369 1 5 8 3 ATÓM 2163 FE IUM 312 8574 13.466 54.055 1.000 11. 05 Anisa 2163 FE IUM 312 1690 1156 1351 -101 -237 7 1 ATÓM 2164 Cl AKG 313 5987 14.815 54.612 1.000 19.65 Anisa 2164 Cl AKG 313 2777 2119 2572 258 -117 5 5 6 ATÓM 2165 01 AKG 313 4.799 15.240 54.659 1.000 20.82 Anisa 2165 01 AKG 313 2957 2293 2659 514 -233 2 6 4 ATÓM 2166 02 AKG 313 6643 14.144 53.787 1.000 17.79

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 161 -

Anisa 2166 02 AKG 313 2407 1765 2 5 8 7 74 -377,429 ATÓM 2167 C2 AKG 313 6.867 15.178 55.844 1,000 ^ 0.08 Anisa 2167 C2 AKG 313 1997 2566 3068 -528 419–3 9 9 ATÓM 2168 05 AKG 313 7.982 14.661 55.821 1,000 17.60 Anisa 2168 05 AKG 313 2289 2066 2234 -314 226 - 2 6 2 ATÓM 2169 C3 AKG 313 6.272 16.080 56872 1,000 2 1.69 Anisa 2169 C3 AKG 313 2751 1910 3581 240 63 - 3 2 7 ATÓM 2170 C4 AKG 313 7.318 16.741 57.716 1,000 2 1.50 Anisa 2170 C4 AKG 313 3246 1761 3160 199 -143 - 18 5 ATÓM 2171 C5 AKG 313 6923 17.816 58.672 1,000 22:58 Anisa 2171 C5 AKG 313 3122 1840 3618 755 -495- 3 1 3 ATÓM 2172 03 AKG 313 7754 18.591 59124 1,000 27.48 Anisa 2172 03 AKG 313 3581 2470 4389 -34 602 -1266 ATÓM 2173 04 AKG 313 5.660 17.889 58.999 1,000 28.55 Anisa 2173 04 AKG 313 3191 2809 4846 612 -246 - 11 14 8 ATÓM 2174 WITH SO4 401 11.676 0439 24.942 1,000 4 0.14 ATÓM 2175 01 SO4 401 11.293 0826 26.321 1,000 3 3.12 ATÓM 2176 02 SO4 401 -12,501 -0,829 25.014 1,000 3 5.79 ATÓM 2177 03 SO4 401 10.430 0189 24.129 1,000 5 4.89 ATÓM 2178 04 SO4 401 12,500 1.520 24.329 1,000 44.80 ATÓM 2179 OW HOH 501 -6,455 10.219 44.319 1,000 14:29 ATÓM 2180 OW HOH 502 -10,520 18.612 50560 1,000 12.86 ATÓM 2181 OW HOH 503 -8,644 16.907 47.858 1,000 16.83 ATÓM 2182 OW HOH 504 -10,313 20.800 43.074 1,000 16:10 ATÓM 2183 OW HOH 505 -6,051 19.199 52.602 1,000 16:38 ATÓM 2184 OW HOH 506 -6,873 24.642 47.100 1,000 20:55 ATÓM 2185 OW HOH 507 10.676 -4,179 46406 1,000 27.41 ATÓM 2186 OW HOH 508 -0.077 21.786 40.872 1,000 15:22 ATÓM 2187 OW HOH 509 5.761 13.656 46.041 1,000 17:40 ATÓM 2188 OW HOH 510 29.135 31.449 51982 1,000 18:40 ATÓM 2189 OW HOH 511 26032 32.724 52.741 1,000 3.17 ATÓM 2190 OW HOH 512 10.965 32.371 46.000 1,000 16.70 ATÓM 2191 OW HOH 513 23.871 24.457 58.649 1,000 18.71 ATÓM 2192 OW HOH 514 26.353 29.063 50.326 1,000 18.96 ATÓM 2193 OW HOH 515 23191 33.106 53.153 1,000 20:41 ATÓM 2194 OW HOH 516 21.429 11.721 55.329 1,000 18:39 ATÓM 2195 OW HOH 517 9.122 15.567 53.585 1,000 24.87 ATÓM 2196 OW HOH 518 27.843 17.352 53.437 1,000 27.76 ATÓM 2197 OW HOH 519 -14,415 20.029 44.444 1,000 23:47 ATÓM 2198 OW HOH 520 15.253 33.050 51771 1,000 27.20 ATÓM 2199 OW HOH 521 14.080 31486 44.302 1,000 21:58 ATÓM 2200 OW HOH 522 17.770 33842 53.596 1,000 23:56 ATÓM 2201 OW HOH 523 3671 24.673 36.173 1,000 20.95 ATÓM 2202 OW HOH 524 -15,683 28.618 52535 1,000 24.05 ATÓM 2203 OW HOH 525 -5,386 20.413 39.013 1,000 26.85 ATÓM 2204 OW HOH 526 10.417 27.949 58.778 1,000 28.33 ATÓM 2205 OW HOH 527 23.165 19.592 62202 1,000 29.36 ATÓM 2206 OW HOH 528 23.736 10.550 55.737 1,000 24.02 ATÓM 2207 OW HOH 529 -1,662 28.650 42.485 1,000 2 1.62 ATÓM 2208 OW HOH 530 -4,689 10.177 46.511 1,000 3 1.65 ATÓM 2209 OW HOH 531 1,545 35657 50.866 1,000 19:59 ATÓM 2210 OW HOH 532 0.980 22.687 36818 1,000 30.57 ATÓM 2211 OW HOH 533 -12,450 16.848 56071 1,000 8.42 ATÓM 2212 OW HOH 534 -9,418 16.139 51.364 1,000 22.60 ATÓM 2213 OW HOH 535 32.711 25.816 43.116 1,000 3 1.44 ATÓM 2214 OW HOH 536 27.068 24.587 55.468 1,000 2 3.32 ATÓM 2215 OW HOH 537 13.523 11.832 51.199 1,000 10.73 ATÓM 2216 OW HOH 538 8.513 16.158 35.074 1,000 12:26 ATÓM 2217 OW HOH 539 0922 2.590 35.058 1,000 14.79 ATÓM 2218 OW HOH 540 -1,548 3,709 34.484 1,000 14:25 ATÓM 2219 OW HOH 541 11.711 16.898 30.416 1,000 i 17.84

SUBSTTTUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 162-

ATÓM 2220 OW HOH 542 15.389 11.536 ATÓM 2221 OW ΗΟΗ 543 18.496 6.995 ATÓM 2222 OW ΗΟΗ 544 19.848 22.580 ATÓM 2223 OW HOH 545 -0,387 4787 ATÓM 2224 OW HOH 546 23.502 12.662 ATÓM 2225 OW HOH 547 10.332 25.236 ATÓM 2226 OW HOH 548 21.447 20.605 ATÓM 2227 OW HOH 549 8164 7.685 ATÓM 2228 OW HOH 550 14.393 -5,127 ATÓM 2229 OW HOH 551 12.873 29356 ATÓM 2230 OW HOH 552 11.974 24144 ATÓM 2231 OW HOH 553 17.521 7.949 ATÓM 2232 OW HOH 554 3401 2,691 ATÓM 2233 OW HOH 555 18669 28.057 ATÓM 2234 OW HOH 556 10.827 12.928 ATÓM 2235 OW HOH 557 20.630 16.270 ATÓM 2236 OW HOH 558 11.315 20266 ATÓM 2237 OW HOH 559 26277 14.516 ATÓM 2238 OW HOH 560 9616 15.488 ATÓM 2239 OW HOH 561 8.888 4,903 ATÓM 2240 OW HOH 562 20.496 -1,851 ATÓM 2241 OW HOH 563 17.033 29.415 ATÓM 2242 OW HOH 564 18.595 6141 ATÓM 2243 OW HOH 565 22.446 13.893 ATÓM 2244 OW HOH 566 6586 3577 ATÓM 2245 OW HOH 567 6.250 20.077 ATÓM 2246 OW HOH 568 7341 16.113 ATÓM 2247 OW HOH 569 16.090 32.070 ATÓM 2248 OW HOH 570 11,500 28.806 ATÓM 2249 OW HOH 571 12.901 26.768 ATÓM 2250 OW HOH 572 -17,071 17.043 ATÓM 2251 OW HOH 573 25262 7.705 ATÓM 2252 OW HOH 574 32884 26.440 ATÓM 2253 OW HOH 575 -1,199 19.088 ATÓM 2254 OW HOH 576 -4,389 33.026 ATÓM 2255 OW HOH 577 17.569 25.732 ATÓM 2256 OW HOH 578 -19,107 12.822 ATÓM 2257 OW HOH 579 29.333 19.198 ATÓM 2258 OW HOH 580 27.950 27.635 ATÓM 2259 OW HOH 581 -21,085 14.501 ATÓM 2260 OW HOH 582 1.529 17,378 ATÓM 2261 OW HOH 583 9.138 20.887 ATÓM 2262 OW HOH 584 -11,896 19091 ATÓM 2263 OW HOH 585 6382 12.597 ATÓM 2264 OW HOH 586 17.762 21268 ATÓM 2265 OW HOH 587 -11,500 25.438 ATÓM 2266 OW HOH 588 7.877 1,046 ATÓM 2267 OW HOH 589 27.985 13.540 ATÓM 2268 OW HOH 590 1,276 14.852 ATÓM 2269 OW HOH 591 24.622 24.179 ATÓM 2270 OW HOH 592 0404 14.096 ATÓM 2271 OW HOH 593 -2,835 36.981 ATÓM 2272 OW HOH 594 3.276 0788 ATÓM 2273 OW HOH 595 11.025 -8,794 ATÓM 2274 OW HOH 596 6301 2,276 ATÓM 2275 OW HOH 597 29.302 16.146 ATÓM 2276 OW HOH 598 19.039 20964 ATÓM 2277 OW HOH 599 8.380 22.088 ATÓM 2278 OW HOH 600 21.480 10.826 ATÓM 2279 OW HOH 601 -2,907 21.956 ATÓM 2280 ow HOH 602 -3,928 29.841

32,065 52,191 35,334 41,967 35,308 33,926 34,090 27,077 40,321 39,662 58,426 33,182 43,340 40,079 30,017 66,466 64,044 43,946 32,365 27,857 42,511 38,332 37,697 31,420 28,350 30,961 31,186 42,552 37,258 58,591 50,450 37,199 51,734 42,527 63,392 32,249 67,516 51,975 51,903 68,535 33,953 66,894 44,780 43,347 29,046 41,729 29,689 42,235 34,021 41,242 36.006 57.827 39.940 31.468 42.639 62.924 67.011 64.518 34.742 38.566 43 .352

1,000 1 7. 8 8 1,000 »4 7 1,000 1 7. 2 8 1-.000 1 3. 2 2 1,000 1 8. 1 4 1,000 1 9. 0 5 1,000 1 7. 2 4 1,000 2 5. 4 0 1,000 1 5. 8 8 1,000 1 6. 4 5 1,000 1 9. 7 1 1,000 1 7. 9 0 1,000 2 3. 7 6 1,000 1 8. 4 4 1,000 1 9. 5 7 1,000 2 0. 8 4 1,000 2 1. 6 2 1,000 1 6. 2 2 1,000 1 9. 4 0 1,000 2 2. 7 4 1,000 2 2. 9 8 1,000 2 6. 3 6 1,000 2 5. 1 0 1,000 2 9. 00 1,000 2 7. 82 1,000 2 3. 27 1,000 2 8. 59 1,000 3 3. 08 1,000 2 5. 17 1,000 2 8. 58 1,000 2 8. 82 1,000 3 9. 05 1,000 2 9. 03 1,000 1 4. 86 1,000 2 9. 56 1,000 2 0. 62 1,000 2 2. 3 5 1,000 2 2. 5 1 1,000 2 5. 40 1,000 2 1. 19 1,000 2 5. 29 1,000 3 3. 92 1,000 1 7. 48 1,000 2 2. 09 1,000 2 0. 79 1,000 2 9. 68 1,000 2 7. 7 0 1,000 2 5. 91 1,000 2 0. 4 1 1,000 2 6. 7 7 1,000 2 7. 92 1,000 3 1. 86 1,000 3 2. 07 1,000 2 7. 1 8 1,000 2 9. 7 4 1,000 4 3. 7 5 1,000 3 0. 8 5 1,000 4 2. 62 1,000 2 5. 7 4 1,000 3 : 0. 92 1,000 4 . 3. . 9 6

SUBSTITUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 163 -

ATÓM 2281 OW HOH 603 2,885 21.563 34437 1,000 3 3. 1 0 ATÓM 2282 OW HOH 604 11.801 6043 25.270 1,000 1 8 ATÓM 2283 OW HOH 605 -1,019 17.197 40.472 1,000 1 8. 4 8 ATÓM 2284 OW HOH 606 18.382 23.349 68110 1,000 2 2. 5 4 ATÓM 2285 OW HOH 607 -8,141 8.137 45.609 1,000 17. 6 4 ATÓM 2286 OW HOH 608 5022 2.667 51.700 1,000 2 4. 2 9 ATÓM 2287 OW HOH 609 17.557 10.755 33.490 1,000 2 1. 9 4 ATÓM 2288 OW HOH 610 11.222 1.201 49.675 1,000 2 0. 6 1 ATÓM 2289 OW HOH 611 4243 35047 50509 1,000 22nd 1 8 ATÓM 2290 OW HOH 612 11.103 4031 56082 1,000 22nd 08 ATÓM 2291 OW HOH 613 11.366 31.522 36.791 1,000 3 2. 3 2 ATÓM 2292 OW HOH 614 -21,189 24.787 52739 1,000 3 1. 8 3 ATÓM 2293 OW HOH 615 7.847 -1,491 30.674 1,000 24. 77 ATÓM 2294 OW HOH 616 19.041 11.937 31.445 1,000 25. 97 ATÓM 2295 OW HOH 617 6.221 29.879 40.410 1,000 2 9. 24 ATÓM 2296 OW HOH 618 17.266 5.933 35.280 1,000 23. 72 ATÓM 2297 OW HOH 619 5.983 -7,215 28.510 1,000 2 8. 1 9 ATÓM 2298 OW HOH 620 22.574 8.129 57.639 1,000 30. 9 7 ATÓM 2299 OW HOH 621 2.553 7806 60287 1,000 28. 77 ATÓM 2300 OW HOH 622 29.939 25.812 51234 1,000 34. 00 ATÓM 2301 OW HOH 623 2.205 34823 53632 1,000 25. 88 ATÓM 2302 OW HOH 624 18.091 13.838 67343 1,000 28. 4 6 ATÓM 2303 OW HOH 625 8342 3.195 58.475 1,000 26. 8 4 ATÓM 2304 OW HOH 626 -16,086 18.427 42790 1,000 3 1. 11 ATÓM 2305 OW HOH 627 -2,098 13.445 35.620 1,000 27 Mar: 48 ATÓM 2306 OW HOH 628 0481 30.471 42. B34 1,000 32. 5 5 ATÓM 2307 OW HOH 629 13.368 33845 42.399 1,000 2 8. 7 0 ATÓM 2308 OW HOH 630 -13,792 14642 51.533 1,000 25. 58 ATÓM 2309 OW HOH 631 3.299 1.461 29242 1,000 39. 62 ATÓM 2310 OW HOH 632 -16,012 20.690 46.705 1,000 27 Mar: 75 ATÓM 2311 OW HOH 633 19.606 8.142 31.259 1,000 27 Mar: 02 ATÓM 2312 OW HOH 634 5077 7954 57.205 1,000 3 0. 5 9 ATÓM 2313 OW HOH 635 -1,502 6.963 45.877 1,000 35. 68 ATÓM 2314 OW HOH 636 9.974 17.449 38804 1,000 2 1. 84 ATÓM 2315 OW HOH 637 -22,829 12.836 67228 1,000 25. 04 ATÓM 2316 OW HOH 638 6275 34.333 39.722 1,000 25. 8 8 ATÓM 2317 OW HOH 639 2.248 19.798 56051 1,000 26. 67 ATÓM 2318 OW HOH 640 -20,552 17.013 67454 1,000 31. 3 4 ATÓM 2319 OW HOH 641 9298 16.570 28.S11 1,000 2 9. 9 6 ATÓM 2320 OW HOH 642 -1,732 11.113 60074 1,000 28. 1 3 ATÓM 2321 OW HOH 643 34.157 23.604 44.657 1,000 3 6. 3 6 ATÓM 2322 OW HOH 644 24.298 20.199 33.576 1,000 34. 90 ATÓM 2323 OW HOH 645 13.803 -4,667 31.570 1,000 32. 66 ATÓM 2324 OW HOH 646 6295 -2,594 29.009 1,000 34. .61 ATÓM 2325 OW HOH 647 5.623 37.039 49.318 1,000 2 8. 08 ATÓM 2326 OW HOH 648 -18,805 19.286 46.868 1,000 38. . 32 ATÓM 2327 OW HOH 649 16.026 35.829 49382 1,000 34. . 4 5 ATÓM 2328 OW HOH 650 -12,187 28.769 45.330 1,000 27 Mar: . 3 6 ATÓM 2329 OW HOH 651 21.344 5.778 55.101 1,000 27 Mar: . 4 3 ATÓM 2330 OW HOH 652 -1,848 2.125 32.240 1,000 32. . 02 ATÓM 2331 OW HOH 653 -14,568 18.811 55775 1,000 29 . 95 ATÓM 2332 OW HOH 654 -8,655 26254 38.301 1,000 32 . 07 ATÓM 2333 OW HOH 655 18836 13.542 28.102 1,000 32 . 2 4 ATÓM 2334 OW HOH 656 16.217 14.669 25.619 1,000 3 3 . 3 5 ATÓM 2335 OW HOH 657 28,678 14.477 38.043 1,000 3 0 . 9 4 ATÓM 2336 OW HOH 658 -11,834 15.408 53.330 1,000 3 3 . 2 5 ATÓM 2337 OW HOH 659 -1,317 38.273 59.599 1,000 i 3 4 . 4 5 ATÓM 2338 OW HOH 660 8.784 13.918 28.631 1,000 i 33 . 62 ATÓM 2339 OW HOH 661 -3,058 14.508 47.405 1,000 i 2 8 . 7 9 ATÓM 2340 OW HOH 662 10.968 33.651 38.533 1,000 1 3 6 . 2 1 ATÓM 2341 OW HOH 663 28.960 21.602 53,665 1,000 1 2 9 . 2 5

SUBSTTrUTE SHEET (RULE 26)

WO 99/33994

PCT / GB98 / 03860

- 164-

ATÓM 2342 OW HOH 664 -10,709 26.808 39.175 1,000 4 2. ATÓM 2343 ow HOH 665 17.790 7,093 55.023 1,000 3 * 0.- » ATÓM 2344 OW HOH 666 6404 24865 29.848 1,000 3 4. ATÓM 2345 ow HOH 667 -15,418 19.777 58.341 1-. 000 3 3. ATÓM 2346 ow HOH 668 0.000 0.000 37.259 0.330 4 9. ATÓM 2347 ow HOH 669 19.652 24.610 33.660 1,000 3 1. ATÓM 2348 ow HOH 670 17.188 9.619 29.950 1,000 2 9. ATÓM 2349 ow HOH 671 17.708 2.958 28.338 1,000 3 4. ATÓM 2350 ow HOH 672 -0.059 3.652 30.079 1,000 3 2. ATÓM 2351 ow HOH 673 29.037 20.923 56.153 1,000 2 8. ATÓM 2352 ow HOH 674 -15,435 31.088 53795 1,000 3 5. ATÓM 2353 ow HOH 675 -12,846 21.220 61856 1,000 3 8. ATÓM 2354 ow HOH 676 10.299 39.666 49.554 1,000 4 0. ATÓM 2355 ow HOH 677 -5,921 28822 41.521 1,000 3 4. ATÓM 2356 ow HOH 678 6029 39.991 46.094 1,000 4 2. ATÓM 2357 ow HOH 679 35052 23.156 52356 1,000 4 0. ATÓM 2358 ow HOH 680 -12,008 38.355 51.601 1,000 3 5. ATÓM 2359 ow HOH 681 3,061 13.047 53.152 1,000 3 5. ATÓM 2360 ow HOH 682 1,379 2.075 27.532 1,000 4 6. ATÓM 2361 ow HOH 683 -0,516 -2,480 37.686 1,000 2 1. ATÓM 2362 ow HOH 684 4567 10.310 43.503 1,000 2 4. ATÓM 2363 ow HOH 685 19.443 5.558 61133 1,000 3 6. ATÓM 2364 ow HOH 686 3205 29.499 40.656 1,000 3 6. ATÓM 2365 ow HOH 687 32.498 16.774 43.447 1,000 4 1. ATÓM 2366 ow HOH 688 28166 23.113 57.593 1,000 3 5. ATÓM 2367 ow HOH 689 -17,023 23.220 46.759 1,000 3 0. ATÓM 2368 ow HOH 690 15.567 7782 28.910 1,000 32. ATÓM 2369 ow HOH 691 11.780 30287 57.203 1,000 33. ATÓM 2370 ow HOH 692 24.449 12.699 32.400 1,000 3 4. ATÓM 2371 ow HOH 693 26.200 25.005 57.918 1,000 3 9.

SUBSTrrUTE SHEET (RULE 26)

Claims (26)

PATENT CLAIMS Deacetoxycephalosporin C synthesis (DAOCS) having the structure determined by the X-ray coordinate of structure A or structure B herein. 2. Deacetoxycephalosporin C synthesis in the form of a complex with a metal, e.g. iron or lead, and optionally in the presence of a substrate and / or an analog substrate or inhibitor, having the structure determined herein by the X-ray coordinate herein. Deacetoxycephalosporin C synthesis according to claim 2, characterized in that the substrate is penicillin N, penicillin G, 2-oxoglutaral. or a dioxygen, and the inhibitor is selected from N-oxalylamino acids, pyridine carboxylates and nitrogen oxide. Use of a three-dimensional structure of deacetoxycephalosporin C synthase for modifying deacetoxycephalosporin C synthase or other related 2-oxoglutarate-dependent enzyme. Use according to claim 4, characterized in that the related 2-oxoglutarate-dependent enzyme is deacetylcephalosporin C synthesis, deacetoxy / deacetylcephalosporin C synthesis or an oxygenase enzyme involved in the incorporation of the 7α-methyloxy group into cefamycin C. The use of claim 5 for modifying a deacetoxycephalosporin C synthase, a deacetylcephalosporin C synthase or a deacethoxy / deacetylcephalosporin C synthase to accept non-natural substrates more efficiently than the unmodified type of enzymes. Use according to claim 5 for the modification of deacetoxycephalosporin C synthase, deacetylcephalosporin C synthase, deacetoxy / deacetylcephalosporin C synthase so that they convert natural substrates into pharmaceuticals or semi-products useful in the preparation of pharmaceuticals. 166 Use according to claim 6, characterized in that the non-natural substrates are penicillins including penicillin G, penicillin V, 6-aminopenicillanic acid, amoxycillin, or phenyl-glycine or p-hydroxyphenyl-glycine side chain penicillins. Use according to claim 6, characterized in that the non-natural substrate is cephalosporin. Use according to claim 6, characterized in that the non-natural substrate is an amino acid, including proteinogenic amino acids, or a peptide. Use according to any one of claims 6 to 8, characterized in that penicillin G, penicillin V, another non-natural substrate or penicillin N is converted to cephalosporin or cephalosporin exomethylene. An enzyme having significant (as defined herein) sequence similarity to a deacetoxycephalosporin C synthase, wherein the penicillin N or deacetoxycephalosporin C side chain binding site is modified and at least one of the following sites of at least one amino acid residue is changed to another amino acid residue or deleted: Thr72, Arg74, Arg75, Glu156, Leu158, Arg160, Arg162, Leu186, Ser187, Phe225, Phe264, Arg266, Asp301, Tyr302, Val303, Asn304; and / or at least one additional amino acid residue is incorporated into region 300-311; with the proviso that another residue interacting with the above may be altered to accommodate the change of one of the above residues. 13. An enzyme having significant (as defined herein) sequence similarity to deacetoxycephalosporin C synthase, characterized in that the binding site of penicillin N or deacetoxycephalosporin 0 is modified and at least one of the following sites of at least one amino acid residue is altered or deleted: Ile88, Arg160, Arg162, Phe164, Met180, Thr190, Ile192, Phe225, Pro241, Val245, Val262, Phe264, lle305, Arg306, Arg307; and / or at least one additional C 7 amino acid residue is incorporated into region 300-311; with the proviso that another residue interacting with the above may be altered to accommodate the change of one of the above residues. The enzyme of claim 12 or claim 13, which is a mutant of deacetoxycephalosporin C synthase or deacetylcephalosporin C synthase or deacethoxy / deacetylcephalosporin C synthase. The enzyme according to any one of claims 12 to 14, characterized in that both the side chain and the penicillin / cephalosporin binding sites of penicillin N or deacetoxycephalosporin C are modified and at least one of the residues specified in claims 12 and 13 is altered or deleted. 16. The enzyme of any one of claims 12 to 15, wherein two or more additional mutations are introduced to create or abrogate the binding interaction, including H-bonds, electrostatic or hydrophobic interactions. A gene encoding an enzyme of any one of claims 12 to 16. A microorganism capable of expressing the gene of claim 17 under fermentation conditions. Use of microorganisms according to claim 18 for the production of beta-lactams from the group of penicillin or cephalosporin (including cephar). Use according to claim 19, characterized in that the microorganism comprises another modified enzyme of the method of penicillin and cephalosporin biosynthesis including isopenicillin N synthase, amidchydrolase / acetyltransferase, or L-delta- (aminoadipoyl) -L-cysteine-D-valine (ACV) synthase. A method comprising using the three-dimensional structure of a deacetoxycephalosporin C synthase to determine or predict the structure of another related 2-oxoglutarate-dependent enzyme or related enzyme not from method w biosynthesis of penicillin and cephalosporin, and the use of structural information thus obtained to modify other enzymes or to design an inhibitor for another enzyme. 22. The method of claim 21, wherein said other related 2-oxoglutarate-dependent enzyme is 1-aminocyclopropane-1-carboxylate oxidase, giberelin C-20 oxidase, flavone synthase, flavanone 3β-hydroxylase, hyoskylamine 6β-hydroxylase prolyl 4-hydroxylase, prolyl 3-hydroxylase, aspartyl hydroxylase, lysyl hydroxylase, proline hydroxylase, γ-butyrobetaine hydroxylase, enzymes in herbicide resistant mechanisms, clavaminate synthase, enzyme oxygenase involved in carbapenem biosynthesis, so-called. ethylene generating enzyme from Pseudomonas syringe, p-hydroxyphenylpyuvate, and oxygenase enzyme involved in the oxidation of phytol in human liver peroxisomes. The method of claim 21 or 22, wherein said other enzyme is modified, deleted or added or altered; at one or more of the sites defined in claim 12 or claim 13; or using design information or inhibitor: Asp185, His183 and His243 acting as iron ligands; Arg258 and Ser260 and iron coupled to 2-oxoglutarate; Met180, Phe225, Leu31 and Val245 are close to the iron binding site; tyr33, Arg160, Arg162, Phe164, Ile192, Gln'94, leu204, Leu223, Leu215 are important for the construction of the active 2-oxoglutarate binding site portion; and Arg 160 and Arg 162 are important for binding an amino acid or peptide-derived substrate. The method of any one of claims 21 to 23, wherein said other enzyme is prolyl 4-hydroxylase, prolyl 3-hydrolase, aspartyl hydrolase, or lysyl hydrolase, and the inhibitor will be used to treat human disease including fibrotic diseases including liver cirrhosis or arthritis. 25. The method of any one of claims 21 to 23, wherein said other related enzyme is p-hydroxyphenylpyruvate dioxygenase and the inhibitor will be used to treat certain genetic disorders. 163 A method according to any one of claims 21-23, characterized in that said other related enzyme induces herbicidal resistance and this information will be used to design new herbicides that overcome the resistance problem.