アクテムラインタビューフォーム

2009 2 6 876399 IF 1998 9 FAX 80mg 1 4mL 80mg 200mg 1 10mL200mg 400mg 1 20mL400mg JAN TocilizumabGenetical RecombinationJAN 200mg 80400mg 2007 9 10 2008 4 16 2007 12 21 2008 6 13 2005 6 13 2008 6 13 2009 2

IF 1 MR 63 IF 10 IF 2IF IF IF 3IF 4 9 IF IF IF 11 1 IF IF 4IF IF MR IF IF MR Drug Safety Update IF

1 1 18 18 3 3 19 3 22 3 23 3 23 3 24 CAS 3 24 25 4 4 26 4 27 4 4 27 27 5 27 5 5 28 6 33 6 34 6 57 6 10 57 6 11 58 7 12 58 107 13 58 117 14 58 15 59 8 16 63 9 11

64 65 66 66 66 66 66 66 66 66 67 10 67 11 67 1267 1367 1468 1568 69 70 71 72

IgG1 6IL-6 CDR IL-6 IgG1 CHO IL-6 1982 B 1986 IL-6 IL-6 1999 IL-6 IL-6 2005 4 2008 4 C 2 1 IL-6 2RA MTX 24 ACR5070 49.2%29.5% DAS 28ESR 2.6 43.1% 1ACR205070 20%50%70% VASVAS VASHAQ CRP ~ 5 3 2DASdisease activity score CRPVAS 28 DAS28 1

DMARDs 52 23.6% ACR70 6 3 X 44 1 5 2 42 0 4 3sJIA JIA305070 91.185.767.9% 4JIA305070 JIA JIA 30%50%70% 6 3 30%50%70%30% 1 30% VAS/VASCHAQ ESR 4pJIA JIA305070 94.794.757.9% 5 C CRP ESR 6 35 601 19 128 783 751 95.9% 421 53.8 292 37.3%LDL 148 18.9% 126 16.1%ALT(GPT) 119 15.2% 2

80mg 200 mg 400 mg ACTEMRA 80 mg for Intravenous Infusion ACTEMRA 200 mg for Intravenous Infusion ACTEMRA 400 mg for Intravenous Infusion acteffective JAN TocilizumabGenetical RecombinationJAN tocilizumabr-inn 214 2 447448 449 2 C1033H1606N278O337S6 C2181H3398N582O672S15 148,000 214 C1033H1606N278O337S623,503.86 2 447448 449 C2181H3398N582O672S1549,004.79 2 148,000 MRA 375823-41-9 3

ph6.07.0 50 24 5 6 40 3 120 luxhr 5 200Whr/m 2 (1) SDS- (2) 4

1 80mg80mg 200 mg200mg 400 mg400mg ph6.07.0 0.51.0 80mg 200mg 400mg 4 ml 10 ml 20 ml 80 mg 200 mg 400 mg 1 80 200 mg 2 mg 500 mg 5 mg 1000 mg 10 mg ) 25kg 50mL25kg 100250mL 20mg/mL 25kg 50mL25kg 100250mL 5

(kg) 8 (mg/kg) (ml) = 20 (mg/ml) 1) [ ] 2) 80mg200mg400mg 5 24 25 6 40 3 120 luxhr 5 200Whr/m 2 200mg 0.1 mg/ml 8 mg/ml 24 6

SDS- 7

C 1 1. 2. MASMAS MAS MAS MAS pjia 1. sjia IL-6 sjia 2.sJIA MAS MAS IL-6 TNF-IFN-IL-1IL-8 MAS MAS MAS 8

MAS MAS MAS MAS NSAIDs ) MAS PLT FDP-ED-dimer 2- AST/LDH/CK ) : 2007 :, 111(8), 1103, 2007 1 8 mg/kg 4 1 8mg/kg 2 1 1-15 (1) sjia 1 23 sjia 2 CRP* IL-6 3 CRP* CRP* *C 9

sjia MAS 1 8mg/kg 2 CRP IL-6 1 8mg/kg 2 1 CRP CRP CRP mg/kg/ CRP CRP log r=-0.707 CRP CRP IL-6 CRP 4 20 mg/ml 25 kg 50 ml25 kg 100 250mL (ml) = (kg) 8 (mg/kg) 20 (mg/ml) 5 (1) (2) 1 (1) 1.2 ((2)2) ) (2) Infusion Reaction 10

1 Infusion Reaction (2) 10mL/hr 15 1 1 25kg 50mL 1 25kg 100mL 1 1 RA P 25.0% MTX8mg/ 16/64 MTX ACR 64 #1 20% 0.001 RA 24 8mg/kg/4 MTX 80.3% MTX 49/61 61 DMARDs RA Total 52 #2 6.12 143 2.5 8mg/kg/4 2.34 157 0.5 0.001 #1: ACR #2: 2 pjia JIA 30% 50% 70% JIA #3 94.7% 94.7% 57.9% pjia 12 18/19 18/19 11/19 #3:Giannini JIA 11

3 sjia P 8mg/2 3 2 sjia 43 23 8mg/kg/2 6 20 17.4% 4/23 80.0% 16/20 0.001 sjia 56 8mg/kg 2 3 JIA 30% CRP0.5mg/dL 6 2 JIA 30% CRP1.5mg/dL 4 8mg/kg 2 248mg/kg/2 CRP 3 7 CRP ESR Hb 8mg/kg/2 8 28 8mg/kg 2 1568 8mg/kg/2 1191 33 1. 1 5 20 0.150.501.02.0mg/kg 1 20 9 45.0% 36 0. 5mg/kg 5 2 40.0%22 1.0mg/kg 5 2 40.0%4 2.0mg/kg 5 5 100.0%10 1 8mg/kg 2. 15 1 5 24 8mg/kg 2 CRP ESR 93.3% 14 /15 2mg/kg 5 37 4mg/kg 5 24 8mg/kg 4 13 74 1 8mg/kg 12

1 163 4mg/kg 8mg/kg 4 3 162 ACR 20%8mg/kg 78.2%43/55 4mg/kg 57.4%31/54 11.3%6/53 8mg/kg 2 P0.0018mg/kg 4mg/kg ACR 50%ACR 70% 8mg/kg 4mg/kg 163 8mg/kg 47/55 85.5% 166 4mg/kg 39/54 72.2% 85 26/54 48.1% 49 HDL ASTALT 4mg/kg 8mg/kg 8mg/kg 4 8mg/kg 1 8mg/kg 2 11 2 2mg/kg CRP 4mg/kg 8mg/kg 3 CRP 2mg/kg/2 CRP 3 4mg/kg/2 5 8mg/kg/2 3 JIA 30%50% 702mg/kg 11 63.6%63.69.1%4mg/kg 8 87.5%87.5%50.0%8mg/kg 3 100%100%100% 11 29 8mg/kg 8mg/kg 2 2 8mg/kg 1 8mg/kg 3 (1) 7 2 2 48mg/kg CRP CRP 8mg/kg 13

2 248mg/kg 7 5 71.4% 18 6 5 83.3% 15 6 4 66.7% 25 8mg/kg 8mg/kg 8mg/kg 2 1 8mg/kg (2) 28 8mg/kg 2 8 28 26 92.9% 160 1 6 16 CRPmg/dL 8.7±5.0 1.2±1.7** 0.9±2.0** mg/dl 639±188 356±149** 317±138** ESRmm/hr 114±34 63±36** 48±40** 0100mm 29.9±22.8 17.4±17.2* 17.7±16.5** Hbg/dL 9.2±2.3 11.6±1.9** 12.0±2.1** g/dl 2.7±0.5 3.6±0.5** 3.7±0.5** 0.05p0.01 t n=24-28sd 1 (1) 8 mg/ + + 8mg/kg/424 ACR 20% 25.0%80.3%P0.001 ADL MHAQ 0.01 14

0.32P0.001MCID (minimum clinically important differences) 0.2234.4% 67.2%P0.001 36.1%22/61 27.9%17/61 16.4%10/61 (2) DMARDs 8 mg/kg/4 DMARD 52 Modified Sharp Score 52 X Total 88.5%139/157 540 P 143 157 3.211.0 0.850.0 0.001 2.911.0 1.490.0 0.024 Total 6.122.5 2.340.5 0.001 2 56 8 mg/kg 2 3 JIA 30% CRP 0.5 mg/dl 43 2 6 12 JIA 30% CRP 1.5 mg/dl JIA 30%5070 91.1% 85.7%67.9% 20 80.0%23 17.4%P0.001 P0.001 15

% χ Log Rank Test: χ 56 53 94.6% 206 184 22 1 2 151 153 8mg/kg 4 3 8mg/kg 24 1 1.86 ± 0.66 mg/kg/mean ± SD 0.7 mg/kg/ 8.2 mg/kg/ 1,394 1,149 3 70.1% ACR ACR 20%70.22 ± 32.32%Mean± SD ACR 50%48.66 ± 39.07%ACR 70%27.94 ±33.88% 150/15398.0%1,320 8 mg/kg 2 118mg/kg 2 11 12010 CRP ESR 90%100%JIA 30%50%70100% 100%90%1 13.68mg 1202.50mg 4 11162 16

15741111 102.5 3 3 8mg/kg 15681191 2218 6 353394.3%460 45221211 1 RA 14MRA 80CrCL 50450 CrCL 30530 CrCL103 2 4 ACR2028.6%4/14 14964.3%18 465360.0%103 266.7%2 2 19 8 mg/kg 4 3 JIA #2 30%50%70% 94.7%94.7%57.9% 19 13 68.4% 21 4 17

6IL-6 IL-6 IL-6R IL-6 gp130 IL-6R IL-6R IL-6 IL-6R gp130 IL-6 1) IL-6 IL-6 in vitro 0.0024g/ IL-6 IL-6R IgG1 IL-6 IL-6 2) IL-6 IL-6 in vitro IL-6 IL-6 IL-6 IL-6 IL-6 3) IL-6 1% 1 IL-6 7 CRP CRP IL-6 1 57 IL-6 4) 18

-1(3) 1 20 1 5 0.150.501.02.0mg/kg 1 Cmax kel CLtotal T1/2 MRT mg/kg n Cmax g/ml AUCfinite hrg/ml T1/2 hr kel /hr CLtotal ml/hr/kg MRT hr Vdss ml/kg 0.15 5 2.4±0.6 11±6 17±16 0.068±0.0459 3.8±2.3 25±22 63.4±16.6 0.50 5 8.5±1.2 285±73 33±4 0.021±0.0028 1.3±0.2 47±5 58.4±7.1 1.0 5 19.5±2.7 1009±222 49±5 0.014±0.0015 0.8±0.1 69±8 57.3±10.9 2.0 5 37.6±8.8 2532±569 74±9 0.009±0.0012 0.6±0.2 107±16 65.9±8.3 AUCfinite SD kel CLtotal MRT Vdss 1 8mg/kg 2 (1) 31 8 mg/kg 1 AUCfinite = 19852 ± 5749hr g/ml ± SDT1/2 = 133 ± 25.7hr CLtotal = 0.4 ± 0.1 ml/hr/kg Vdss= 78.5 ± 16.8 ml/kg 19

) 200 150 100 50 0 0 1 2 3 4 5 (2) 1) 15 1 5 24 8 mg/kg 2 2 CLtotal T1/2 C1hr AUCfinite T1/2 CLtotal MRT Vdss mg/kg g/ml hr g/ml hr ml/hr/kg hr ml/kg 1 3 2 43.6 ± 10.1 3440 ± 823 74 ± 18 0.5 ± 0.2 107 ± 25 55.0 ± 13.0 4 49.0 ± 12.6 4663 ± 2185 97 ± 50 0.9 ± 0.5 138 ± 68 102 ± 24.0 8 82.5 ± 32.4 10661 ± 4070 160 ± 34 0.6 ± 0.2 227 ± 46 137 ± 31.6 2 27.9 ± 12.3 3014 ± 1070 87 ± 18 0.5 ± 0.1 140 ± 26 70.7 ± 13.5 4 49.5 ± 10.1 6035 ± 3200 140 ± 71 0.7 ± 0.5 204 ± 105 98.5 ± 14.6 8 129.9 ± 48.1 19939 ± 8900 242 ± 71 0.3 ± 0.1 343 ± 105 90.9 ± 29.9 4 5 ± SD ) 18 mg/kg 2) 157 8 mg/kg 4 13 1 3 4 12 ± SD 9.8 ± 7.5g/mL6 4 24 12.3 ± 8.6 g/ml 20 20

) 30 20 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 3 19 3 19 12 8 mg/kg 4 3 1 7 3 7 7-15 15 C1hr AUCfinite T1/2 CLtotal MRT g/ml hr g/ml hr ml/hr/kg hr Vdss ml/kg 107.8 ± 15.0 12970 ± 2511 N.A. N.A. N.A. N.A. 158.6 ± 34.4 20878 ± 5328 99 ± 12 0.3 ± 0.0 150 ± 9 48.0 ± 7.0 158.1 ± 36.2 25954 ± 6157 143 ± 43 0.3 ± 0.1 200 ± 49 60.5 ± 12.2 145.0 ± 37.5 25275 ± 6722 123 ± 41 0.3 ± 0.1 178 ± 46 58.3 ± 13.9 ± SDN.A.: 3 7 C1hr AUCfiniten=57 15 :C1hr AUCfiniten=7 n=415 n=7 4 2 19 8 8 mg/kg 2 3 1 6 9 18 3 7 8 14 57.4 g/ml 18 13 21

C1hr AUCfinite T1/2 CLtotal MRT Vdss g/ml hr g/ml hr ml/hr/kg hr ml/kg 2 7 1 142.8 ± 31.6 17677 ± 5193 N.A. N.A. N.A. N.A. 3 171.7 ± 51.2 23706 ± 9704 100 ± 38 0.3 ± 0.1 155 ± 60 45.4 ± 7.6 7 15 1 176.7 ± 48.5 24701 ± 7611 N.A. N.A. N.A. N.A. 3 239.8 ± 70.2 35333 ± 11668 127 ± 26 0.2 ± 0.2 188 ± 49 43.0 ± 17.5 15 1 166.0 ± 31.8 23653 ± 3571 N.A. N.A. N.A. N.A. 3 214.0 ± 40.0 33336 ± 8115 139 ± 30 0.2 ± 0.0 249 ± 21 43.6 ± 11.2 ± SDN.A. (2 7n=19-237 15n=25 2815n=4 5) 5 28 8mg/kg 2 8 1 8 36. 6±17.5µg/mL 6 T1/2 MRT 6 mg/kg C1hr AUCfinite T1/2 CLtotal MRT Vdss g/ml hrg /ml hr ml/hr/kg hr ml/kg 8 1 112.9±24.7 13091.8±3254. 99.7±17. 0.57±0.15 145.4±26.8 80.1±15.0 8 192.3±38.7 28423.2±7410.7 139.0±37.4 0.24±0.08 204.6±54.2 46.8±8.8 26-28±SD -1(3) 22

-1(3) -1(3) 20 50 21050mg/kg 1 1 31 10mg/kg IgG IgG 125 I- 5mg/kg TCA 30 2 14 23

28 125 I- IL-6 14 TCA 125 I- 125 I- IL-6 IgG IL-6 IL-6 IL-6 1 5 20 0.150.501.02.0mg/kg 1 1 8mg/kg 125 I- 5mg/kg 28 74.3% 2.4% TCA 5.24% 24

125 I -6 (1) -6 (1) 25

IL-6 CRP IL-6 1.(3)(7) 2)4) sjia IL-6 (3)(7) 2)4 26

1 2 1 IL-6 EB 1(3)(7) 2)4) 2 80 (1) 1 VI VI (1) [] (2) X [ X ] (3) [] (4) (5) 27

3(5) 3)4) (1) IL-6R 2 1) (2) Infusion Reaction Infusion Reaction Infusion Reaction 201 Infusion Reaction 20 10.0% 7 3.5% 7 3.5% Infusion Reaction Infusion Reaction Infusion Reaction 5 28

(3) 1) 2) 500/L 3) IL-6 1) 2) 500/L 3) 1. 1. 2)4)) (4) CRP X CT IL-6 29

IL-6 CRP 32) CRP sjia pjia 1. 1. 2)4)) (5) X CT TNF- IL-6 IL-6 783 2 (0.3%) 1.52.5 TNF- 12 1 52 IL-6 30

(6) IL-6 6 (7) 783 5 (0.6%) (8) LDL 3 LDL 184.9 mg/dl93.8 mg/dl 108.9 mg/dl 12 Atherogenic index 431 * 177 41.1% 98 22.7% pjia sjia 31

* 601 (9) 3 ALTGPT AST(GOT) DMARD (10) IL-6 IL-6 IL-6 IL-6R IL-6 pjia IL-6 sjia MAS IL-6 20 CRP IL-6 32

(11) 35 QT 1 3 2 5 gp130 gp130 * gp130 IL-6 pjia sjia (MRA213JP) 61 MTX 64 2 2 4 QTc pjia sjia 8 48 601 5 (0.8%) 1 pjia19 sjia 128 0 *(5) 33

35 601 19 128 783 751 95.9% 421 53.8% 292 37.3%LDL 148 18.9% 126 16.1%ALTGPT 119 15.2% 1) (0.4%) ) IL-6R 783 3 0.4% 2-5 2030 5 (1) 2)7.8%6.4%3.4%3.3% 0.9%0.4%0.4%0.3% 0.1% IL-6 3 34

MRA009JP 16.7%(9/54 ) 8mg/kg 23.6%(13/55 ) MRA213JP MTX 25.0%(16/64 ) 39.3%(24/61 )MRA012JP 51.0%(74/145 ) 58.0%(91/157 ) 783 101 (12.9%) 764 260 52 X 3) X CT -- ) 4) X CT ) 4900 8 3 # 6 1 NSAID CRP 35

5) 7.0% 783 55 (7.0%) / 2 sjia NCI 3 1000/L 2635 DMARDs 1000/L 1 77 (2.9%) 2 9 (0.3%) 3 601 3 (0.3%) 3 36

6) ) sjia IL-6 (10) IL-6 (11) 37

5% 1%5% 0.5%1% 90.0% 37.3% LDL HDL LDH ALTGPTAST GOTγ-GTP CKCPK Al-P T ST T TAT FDPD BUN NAG CRP DNA ) G ) ) 2 DNA 217 10 4.6% 0 216 24 11.1% 18 8.3% sjia pjia 4 (0.5%) 38

35 601 19 128 783 33 (94.3) 585 (97.3) 18 (94.7) 115 (89.8) 751 (95.9) 456 4254 85 952 5747 30 (85.7) 469 (78.0) 17 (89.5) 101 (78.9) 617 (78.8) 85 1110 44 398 1637 6 (1.0) 6 (0.8) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 1 (0.8) 3 (0.4) 4 (0.7) 4 (0.5) 4 (0.7) 4 (0.5) 3 (0.5) 1 (0.8) 4 (0.5) 23 (3.8) 2 (10.5) 20 (15.6) 45 (5.7) 1 (2.9) 29 (4.8) 1 (5.3) 7 (5.5) 38 (4.9) 2 (0.3) 2 (0.3) 1 (2.9) 2 (0.3) 3 (0.4) 2 (5.7) 1 (0.2) 3 (0.4) 2 (5.7) 23 (3.8) 1 (0.8) 26 (3.3) 1 (0.2) 1 (0.1) 9 (1.5) 1 (0.8) 10 (1.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 2 (5.7) 43 (7.2) 1 (5.3) 2 (1.6) 48 (6.1) 1 (2.9) 19 (3.2) 1 (5.3) 8 (6.3) 29 (3.7) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 3 (2.3) 3 (0.4) 2 (0.3) 2 (0.3) 2 (5.7) 8 (1.3) 3 (2.3) 13 (1.7) 7 (1.2) 3 (2.3) 10 (1.3) 4 (0.7) 4 (0.5) 2 (5.7) 36 (6.0) 2 (10.5) 41 (32.0) 81 (10.3) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 3 (0.5) 9 (7.0) 12 (1.5) 3 (2.3) 3 (0.4) 39

2 (5.7) 32 (5.3) 1 (5.3) 3 (2.3) 38 (4.9) 7 (1.2) 7 (0.9) 3 (8.6) 41 (6.8) 6 (4.7) 50 (6.4) 3 (8.6) 9 (1.5) 13 (10.2) 25 (3.2) 2 (0.3) 3 (15.8) 11 (8.6) 16 (2.0) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.8) 1 (0.1) 16 (2.7) 1 (5.3) 19 (14.8) 36 (4.6) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 3 (0.5) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (1.6) 2 (0.3) 1 (0.8) 1 (0.1) 2 (5.7) 15 (2.5) 17 (2.2) 27 (77.1) 315 (52.4) 14 (73.7) 65 (50.8) 421 (53.8) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.8) 1 (0.1) 1 (2.9) 1 (0.2) 3 (2.3) 5 (0.6) 1 (0.2) 1 (0.1) 2 (0.3) 2 (1.6) 4 (0.5) 1 (2.9) 11 (1.8) 1 (5.3) 10 (7.8) 23 (2.9) 3 (0.5) 1 (0.8) 4 (0.5) 3 (0.5) 3 (0.4) 27 (4.5) 13 (10.2) 40 (5.1) 3 (0.5) 3 (2.3) 6 (0.8) 2 (0.3) 2 (0.3) 5 (0.8) 5 (0.6) 1 (0.8) 1 (0.1) 6 (17.1) 49 (8.2) 5 (26.3) 32 (25.0) 92 (11.7) 2 (5.7) 41 (6.8) 2 (10.5) 10 (7.8) 55 (7.0) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 4 (0.7) 4 (0.5) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.2) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 4 (11.4) 6 (1.0) 9 (7.0) 19 (2.4) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 40

1 (2.9) 22 (3.7) 1 (5.3) 3 (2.3) 27 (3.4) 4 (0.7) 1 (5.3) 2 (1.6) 7 (0.9) 9 (1.5) 7 (5.5) 16 (2.0) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (2.9) 29 (4.8) 30 (3.8) 1 (2.9) 8 (1.3) 1 (5.3) 1 (0.8) 11 (1.4) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 26 (4.3) 6 (31.6) 43 (33.6) 75 (9.6) 4 (11.4) 20 (3.3) 3 (2.3) 27 (3.4) 5 (0.8) 5 (0.6) 4 (0.7) 4 (0.5) 1 (0.2) 2 (1.6) 3 (0.4) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 1 (2.9) 1 (0.1) 2 (5.7) 2 (0.3) 6 (4.7) 10 (1.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) β 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.8) 3 (0.4) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 5 (0.8) 3 (2.3) 8 (1.0) 1 (0.2) 1 (0.8) 2 (0.3) 1 (2.9) 1 (0.1) 2 (5.7) 40 (6.7) 4 (3.1) 46 (5.9) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 3 (0.5) 3 (0.4) 4 (0.7) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 1 (5.3) 5 (0.6) 2 (1.6) 2 (0.3) 41

6 (1.0) 6 (0.8) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 3 (0.5) 3 (0.4) 5 (0.8) 1 (0.8) 6 (0.8) 1 (2.9) 9 (1.5) 10 (1.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 30 (5.0) 2 (1.6) 32 (4.1) 30 2 32 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 2 (1.6) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 3 (8.6) 27 (4.5) 1 (5.3) 9 (7.0) 40 (5.1) 5 28 1 9 43 1 (2.9) 2 (0.3) 3 (2.3) 6 (0.8) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 12 (2.0) 1 (0.8) 13 (1.7) 2 (5.7) 2 (0.3) 5 (0.8) 1 (5.3) 2 (1.6) 8 (1.0) 42

2 (5.7) 4 (0.7) 1 (0.8) 7 (0.9) 1 (0.2) 2 (1.6) 3 (0.4) 1 (2.9) 21 (3.5) 4 (21.1) 7 (5.5) 33 (4.2) 1 21 4 8 34 1 (0.2) 2 (1.6) 3 (0.4) 1 (5.3) 1 (0.8) 2 (0.3) 1 (2.9) 16 (2.7) 3 (15.8) 5 (3.9) 25 (3.2) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 2 (5.7) 7 (1.2) 9 (1.1) 2 7 9 1 (2.9) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 8 (22.9) 35 (5.8) 1 (0.8) 44 (5.6) 9 36 1 46 2 (5.7) 2 (0.3) 4 (0.5) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 10 (1.7) 10 (1.3) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 2 (5.7) 2 (0.3) 1 (0.2) 1 (0.1) 2 (5.7) 13 (2.2) 15 (1.9) 1 (2.9) 15 (2.5) 1 (0.8) 17 (2.2) 1 16 1 18 1 (0.2) 1 (0.1) 1 (2.9) 11 (1.8) 1 (0.8) 13 (1.7) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 9 (25.7) 90 (15.0) 2 (10.5) 15 (11.7) 116 (14.8) 13 111 2 16 142 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 43

1 (0.2) 1 (0.1) 25 (4.2) 1 (0.8) 26 (3.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 6 (17.1) 50 (8.3) 1 (5.3) 13 (10.2) 70 (8.9) 4 (11.4) 12 (2.0) 16 (2.0) 3 (0.5) 1 (0.8) 4 (0.5) 1 (5.3) 1 (0.1) 1 (2.9) 3 (0.5) 4 (0.5) 2 (0.3) 2 (0.3) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 8 (22.9) 93 (15.5) 1 (5.3) 26 (20.3) 128 (16.3) 13 114 1 32 160 1 (2.9) 1 (0.2) 2 (0.3) 2 (1.6) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 4 (0.7) 4 (0.5) 1 (2.9) 1 (0.1) 5 (0.8) 1 (0.8) 6 (0.8) 1 (0.2) 1 (0.1) 1 (2.9) 3 (0.5) 5 (3.9) 9 (1.1) 1 (0.2) 1 (0.1) 4 (11.4) 6 (1.0) 10 (1.3) 1 (2.9) 30 (5.0) 11 (8.6) 42 (5.4) 9 (1.5) 1 (5.3) 3 (2.3) 13 (1.7) 2 (0.3) 1 (0.8) 3 (0.4) 2 (0.3) 2 (0.3) 10 (1.7) 10 (1.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 1 (2.9) 4 (0.7) 1 (0.8) 6 (0.8) 1 (2.9) 2 (0.3) 3 (0.4) 1 (0.2) 2 (1.6) 3 (0.4) 2 (0.3) 1 (0.8) 3 (0.4) 44

1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.2) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 4 (0.7) 4 (0.5) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (2.3) 3 (0.4) 3 (8.6) 23 (3.8) 1 (0.8) 27 (3.4) 3 26 1 30 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 1 (0.8) 4 (0.5) 7 (1.2) 7 (0.9) 4 (0.7) 4 (0.5) 1 (2.9) 3 (0.5) 4 (0.5) 1 (2.9) 5 (0.8) 6 (0.8) 4 (11.4) 29 (4.8) 33 (4.2) 5 33 38 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 9 (1.5) 9 (1.1) 2 (0.3) 2 (0.3) 2 (5.7) 5 (0.8) 7 (0.9) 45

1 (0.2) 1 (0.1) 3 (8.6) 4 (0.7) 7 (0.9) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (8.6) 67 (11.1) 15 (11.7) 85 (10.9) 4 72 16 92 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 2 (1.6) 6 (0.8) 2 (0.3) 2 (0.3) 2 (5.7) 40 (6.7) 11 (8.6) 53 (6.8) 2 (1.6) 2 (0.3) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 5 (0.8) 5 (0.6) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (5.7) 2 (0.3) 4 (0.5) 1 (0.2) 1 (0.1) 18 (51.4) 171 (28.5) 6 (31.6) 40 (31.3) 235 (30.0) 29 213 6 47 295 3 (0.5) 1 (5.3) 1 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 31 (5.2) 1 (0.8) 36 (4.6) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (1.6) 4 (0.5) 4 (0.7) 4 (0.5) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 4 (0.7) 1 (0.8) 6 (0.8) 1 (2.9) 1 (0.1) 1 (0.8) 1 (0.1) 46

7 (20.0) 42 (7.0) 3 (2.3) 52 (6.6) 1 (2.9) 4 (0.7) 5 (0.6) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 9 (1.5) 1 (0.8) 10 (1.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 9 (1.5) 2 (10.5) 8 (6.3) 19 (2.4) 3 (8.6) 6 (1.0) 9 (1.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 5 (14.3) 66 (11.0) 3 (15.8) 27 (21.1) 101 (12.9) 1 (0.2) 1 (0.1) 3 (8.6) 3 (0.5) 2 (1.6) 8 (1.0) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 22 (62.9) 247 (41.1) 9 (47.4) 64 (50.0) 342 (43.7) 46 414 13 93 566 1 (2.9) 4 (0.7) 1 (0.8) 6 (0.8) 7 (1.2) 7 (0.9) 3 (8.6) 13 (2.2) 2 (10.5) 9 (7.0) 27 (3.4) 3 (8.6) 1 (0.8) 4 (0.5) 5 (14.3) 27 (4.5) 2 (1.6) 34 (4.3) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 4 (0.7) 5 (0.6) 17 (2.8) 1 (5.3) 6 (4.7) 24 (3.1) 1 (0.2) 1 (0.1) 6 (1.0) 6 (0.8) 1 (2.9) 26 (4.3) 1 (5.3) 12 (9.4) 40 (5.1) 7 (20.0) 39 (6.5) 2 (10.5) 17 (13.3) 65 (8.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 6 (1.0) 6 (0.8) 10 (1.7) 2 (10.5) 1 (0.8) 13 (1.7) 47

1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 5 (0.8) 5 (0.6) 4 (0.7) 4 (0.5) 1 (2.9) 21 (3.5) 2 (1.6) 24 (3.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 1 (2.9) 1 (0.1) 5 (0.8) 5 (0.6) 13 (2.2) 4 (3.1) 17 (2.2) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 5 (0.8) 2 (1.6) 7 (0.9) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (5.3) 1 (0.8) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 19 (3.2) 1 (5.3) 5 (3.9) 29 (3.7) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 11 (1.8) 11 (1.4) 3 (8.6) 19 (3.2) 5 (3.9) 27 (3.4) 2 (1.6) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 7 (1.2) 8 (1.0) 2 (0.3) 2 (0.3) 1 (2.9) 14 (2.3) 15 (1.9) 5 (14.3) 56 (9.3) 3 (15.8) 11 (8.6) 75 (9.6) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 3 (8.6) 9 (1.5) 1 (0.8) 13 (1.7) 1 (0.2) 1 (0.1) 2 (5.7) 17 (2.8) 7 (5.5) 26 (3.3) 48

1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 4 (0.7) 5 (0.6) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 38 (6.3) 2 (1.6) 44 (5.6) 4 42 2 48 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 1 (0.2) 1 (0.1) 2 (5.7) 3 (0.5) 2 (1.6) 7 (0.9) 2 (5.7) 25 (4.2) 27 (3.4) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 24 (68.6) 223 (37.1) 10 (52.6) 61 (47.7) 318 (40.6) 51 328 11 104 494 1 (2.9) 5 (0.8) 8 (6.3) 14 (1.8) 3 (0.5) 3 (0.4) 1 (2.9) 5 (0.8) 1 (0.8) 7 (0.9) 1 (2.9) 4 (0.7) 5 (0.6) 1 (2.9) 7 (1.2) 2 (1.6) 10 (1.3) 1 (0.2) 2 (1.6) 3 (0.4) 3 (8.6) 12 (2.0) 1 (5.3) 2 (1.6) 18 (2.3) 1 (0.2) 1 (0.1) 3 (8.6) 2 (0.3) 4 (3.1) 9 (1.1) 1 (2.9) 2 (0.3) 3 (0.4) 5 (14.3) 46 (7.7) 4 (21.1) 21 (16.4) 76 (9.7) 9 (1.5) 1 (5.3) 6 (4.7) 16 (2.0) 1 (2.9) 16 (2.7) 2 (1.6) 19 (2.4) 1 (0.2) 2 (1.6) 3 (0.4) 11 (31.4) 56 (9.3) 1 (5.3) 8 (6.3) 76 (9.7) 1 (2.9) 7 (1.2) 8 (1.0) 1 (2.9) 1 (0.1) 1 (5.3) 8 (6.3) 9 (1.1) 2 (0.3) 2 (0.3) 2 (5.7) 2 (0.3) 8 (1.3) 8 (1.0) 8 (1.3) 9 (7.0) 17 (2.2) 1 (2.9) 1 (0.8) 2 (0.3) 49

1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 5 (0.8) 1 (5.3) 1 (0.8) 7 (0.9) 10 (28.6) 45 (7.5) 8 (6.3) 63 (8.0) 7 (1.2) 7 (0.9) 1 (0.2) 1 (0.1) 1 (2.9) 6 (1.0) 7 (0.9) 1 (0.2) 1 (0.1) 1 (2.9) 4 (0.7) 5 (0.6) 1 (0.2) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 1 (2.9) 1 (0.2) 2 (0.3) 1 (0.2) 1 (0.1) 2 (5.7) 20 (3.3) 1 (0.8) 23 (2.9) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 2 (5.7) 15 (2.5) 2 (10.5) 16 (12.5) 35 (4.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.2) 1 (0.1) 10 (28.6) 76 (12.6) 1 (5.3) 13 (10.2) 100 (12.8) 17 86 1 15 119 3 (8.6) 6 (1.0) 9 (1.1) 1 (0.8) 1 (0.1) 1 (0.8) 1 (0.1) 6 (17.1) 15 (2.5) 1 (0.8) 22 (2.8) 1 (2.9) 1 (0.2) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 50

1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 6 (1.0) 2 (1.6) 8 (1.0) 1 (2.9) 2 (0.3) 2 (1.6) 5 (0.6) 11 (1.8) 11 (1.4) 3 (8.6) 5 (0.8) 8 (1.0) 1 (2.9) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 5 (0.8) 1 (5.3) 7 (0.9) 1 (0.2) 1 (0.1) 4 (3.1) 4 (0.5) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 2 (5.7) 29 (4.8) 6 (4.7) 37 (4.7) 2 29 7 38 3 (0.5) 3 (0.4) 2 (0.3) 1 (0.8) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 4 (0.7) 4 (3.1) 8 (1.0) 2 (0.3) 2 (0.3) 4 (0.7) 1 (0.8) 5 (0.6) 1 (2.9) 1 (0.2) 2 (0.3) 2 (0.3) 2 (0.3) 51

1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 4 (11.4) 27 (4.5) 3 (2.3) 34 (4.3) 6 30 3 39 1 (0.8) 1 (0.1) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.2) 2 (0.3) 1 (2.9) 3 (0.5) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 6 (1.0) 6 (0.8) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 21 (60.0) 84 (14.0) 14 (10.9) 119 (15.2) 39 109 18 166 1 (0.2) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 6 (17.1) 5 (0.8) 11 (1.4) 4 (11.4) 12 (2.0) 1 (0.8) 17 (2.2) 2 (5.7) 1 (0.2) 5 (3.9) 8 (1.0) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 3 (8.6) 3 (0.5) 6 (0.8) 1 (2.9) 5 (0.8) 6 (0.8) 3 (8.6) 4 (0.7) 7 (0.9) 52

1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 7 (20.0) 12 (2.0) 2 (1.6) 21 (2.7) 1 (2.9) 1 (0.1) 1 (2.9) 2 (0.3) 3 (0.4) 2 (5.7) 14 (2.3) 2 (1.6) 18 (2.3) 3 (0.5) 3 (0.4) 5 (14.3) 20 (3.3) 6 (4.7) 31 (4.0) 1 (2.9) 1 (0.2) 2 (0.3) 2 (5.7) 3 (0.5) 5 (0.6) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (1.6) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 25 (71.4) 436 (72.5) 2 (10.5) 78 (60.9) 541 (69.1) 120 1390 2 175 1687 1 (2.9) 1 (0.1) 5 (14.3) 87 (14.5) 27 (21.1) 119 (15.2) 4 (11.4) 62 (10.3) 20 (15.6) 86 (11.0) β 8 (6.3) 8 (1.0) 1 (0.2) 1 (0.8) 2 (0.3) 1 (2.9) 29 (4.8) 3 (2.3) 33 (4.2) 1 (2.9) 4 (0.7) 5 (0.6) 2 (0.3) 2 (0.3) 1 (0.8) 1 (0.1) 4 (11.4) 271 (45.1) 17 (13.3) 292 (37.3) 2 (5.7) 11 (1.8) 1 (0.8) 14 (1.8) 3 (0.5) 3 (0.4) 25 (4.2) 25 (3.2) 1 (2.9) 2 (0.3) 3 (0.4) 4 (11.4) 3 (0.5) 7 (0.9) 53

1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 11 (1.8) 10 (7.8) 21 (2.7) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.1) 5 (14.3) 45 (7.5) 17 (13.3) 67 (8.6) 5 (0.8) 4 (3.1) 9 (1.1) 2 (0.3) 2 (0.3) 1 (2.9) 6 (1.0) 1 (0.8) 8 (1.0) 1 (2.9) 1 (0.1) 2 (5.7) 39 (6.5) 1 (0.8) 42 (5.4) 7 (20.0) 7 (0.9) 1 (0.2) 1 (0.1) 7 (20.0) 119 (19.8) 126 (16.1) 2 (5.7) 20 (3.3) 4 (3.1) 26 (3.3) 1 (2.9) 14 (2.3) 15 (1.9) 1 (2.9) 1 (0.1) 4 (0.7) 4 (0.5) 2 (5.7) 4 (0.7) 6 (0.8) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 5 (0.8) 5 (0.6) 1 (2.9) 2 (0.3) 1 (0.8) 4 (0.5) 1 (2.9) 13 (2.2) 14 (1.8) 19 (3.2) 19 (2.4) 2 (5.7) 14 (2.3) 16 (2.0) 2 (0.3) 2 (0.3) 4 (11.4) 2 (0.3) 6 (0.8) 5 (0.8) 5 (0.6) γ 3 (8.6) 53 (8.8) 56 (7.2) 9 (1.5) 6 (4.7) 15 (1.9) 1 (0.2) 1 (0.1) 9 (1.5) 9 (1.1) 1 (0.2) 1 (0.1) 1 (2.9) 20 (3.3) 1 (5.3) 4 (3.1) 26 (3.3) 9 (1.5) 9 (1.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.2) 2 (0.3) 54

1 (2.9) 2 (0.3) 3 (0.4) 1 (2.9) 41 (6.8) 42 (5.4) 1 (0.8) 1 (0.1) 2 (5.7) 146 (24.3) 148 (18.9) 1 (2.9) 11 (1.8) 1 (5.3) 19 (14.8) 32 (4.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 9 (25.7) 32 (5.3) 14 (10.9) 55 (7.0) 5 (0.8) 5 (0.6) 2 (5.7) 14 (2.3) 2 (1.6) 18 (2.3) 10 (1.7) 2 (1.6) 12 (1.5) 3 (0.5) 3 (0.4) 1 (2.9) 1 (0.2) 2 (0.3) 5 (0.8) 5 (0.6) 1 (2.9) 1 (0.1) 6 (1.0) 6 (0.8) 4 (11.4) 2 (0.3) 6 (0.8) 3 (0.5) 3 (0.4) 2 (5.7) 1 (0.2) 3 (0.4) 1 (0.2) 1 (0.1) 4 (0.7) 4 (0.5) 2 (5.7) 62 (10.3) 4 (3.1) 68 (8.7) 2 (5.7) 10 (1.7) 12 (1.5) 3 (8.6) 1 (0.2) 4 (0.5) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 9 (1.5) 9 (1.1) 2 (5.7) 2 (0.3) 4 (0.5) 1 (2.9) 6 (1.0) 7 (0.9) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (0.3) 2 (0.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 1 (2.9) 1 (0.2) 2 (1.6) 4 (0.5) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 2 (5.7) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (8.6) 6 (1.0) 1 (0.8) 10 (1.3) 1 (0.2) 1 (0.1) 1 (2.9) 1 (0.1) 55

3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 3 (0.5) 3 (0.4) 1 (0.2) 1 (0.1) 4 (11.4) 24 (4.0) 4 (3.1) 32 (4.1) 1 (2.9) 1 (0.1) 1 (2.9) 7 (1.2) 8 (1.0) 1 (0.2) 1 (0.1) 6 (1.0) 6 (0.8) 2 (5.7) 2 (0.3) 1 (0.2) 1 (0.1) A 1 (0.2) 1 (0.1) 1 (2.9) 8 (1.3) 3 (2.3) 12 (1.5) 1 9 3 13 1 (0.8) 1 (0.1) 2 (0.3) 2 (0.3) 1 (2.9) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 (0.2) 1 (0.8) 2 (0.3) 1 (0.2) 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.8) 1 (0.1) 1 1 1 (0.8) 1 (0.1) MedDRA/J ver.8.0j 56

0.4% (1) (2) (1) (2)IgG IgG 57

sjia2 7 25 7 15 38 pjia3 7 57 15 7 1) 2) 1) 2) 1.2 3) 1) 80 2) 1) 2) 3) 58

(1) 601 18 3.0% 19 1 5.3%128 11 8.6% 35 1 2.9% pjiasjia 1 IgE 24mg/kg 2 3 79.8 45 364 143 3 59

pjia sjia (%) 601 344 19 128 18 35 1145 % IgE 18 3.0 4 15 25 (7.3) 13 18 1 (5.3) 1 1 11 8.6 0 11 2 (11.1) 2 0 1 2.9 1 1 58 5.1 21 46 pjia ( N=601 N=344 (N=19) IgE IgE IgE 0/601( 0.0) 1/601(0.2) 0/344(0.0) 0/344(0.0) 0/19(0.0) 0/19(0.0) 2(mg/kg) 0/5(0.0) 0/5(0.0) 10/123(8.1) 11/123(8.9) 0/0 0/0 4(mg/kg) 0/59(0.0) 3/59(5.1) 3/112(2.7) 7/112(6.3) 0/0 0/0 8(mg/kg) 4/537(0.7) 11/537(2.0) 0/109(0.0) 0/109(0.0) 1/19(5.3) 1/19(5.3) (%) 4/601(0.7) 15/601(2.5) 13/344(3.8) 18/344(5.2) 1/19(5.3) 1/19(5.3) () sjia ( (N=128) (N=18) (N=35) (%) (N=1145) IgE IgE IgE IgE 0/128(0.0) 0/128(0.0) 0/18(0.0) 0/18(0.0) 0/35(0.0) 0/35(0.0) 0/1145(0.0) 1/1145(0.1) 2(mg/kg) 0/11(0.0) 0/11(0.0) 1/6(16.7) 0/6(0.0) 1/7(14.3) 1/7(14.3) 12/152(7.9) 12/152(7.9) 4(mg/kg) 0/0 0/0 0/6(0.0) 0/6(0.0) 0/6(0.0) 0/6(0.0) 3/183(1.6) 10/183(5.5) 8(mg/kg) 0/117(0.0) 11/117(9.4) 1/6(16.7) 0/6(0.0) 0/35(0.0) 0/35(0.0) 6/823(0.7) 23/823(2.8) (%) 0/128(0.0) 11/128(8.6) 2/18(11.1) 0/18(0.0) 1/35(2.9) 1/35(2.9) 21/1145(1.8) 46/1145(4.0) pjia ( N=601 N=344 (N=19) IgE IgE IgE - 1(0.2) - - - - 1-1(0.2) - 2(0.6) - - 2-4(0.7) - 8(2.3) - - 3-2(0.3) 1(0.3) 6(1.7) 1(5.3) - 4-3(0.5) 12(3.5) 2(0.6) - - 5 * 4(0.7) 4(0.7) - - - 1(5.3) (%) 4(0.7) 15(2.5) 13(3.8) 18(5.2) 1(5.3) 1(5.3) () sjia ( (N=128) (N=18) (N=35) (%) (N=1145) IgE IgE IgE IgE - - - - - - - 1(0.1) 1-7( 5.5) 2( 11.1) - - - 2(0.2) 10(0.9) 2-3( 2.3) - - 1(2.9) 1(2.9) 1(0.1) 16(1.4) 3-1( 0.8) - - - - 2(0.2) 9(0.8) 4 - - - - - - 12(1.1) 5(0.4) 5 * - - - - - - 4(0.4) 5(0.4) (%) - 11( 8.6) 2( 11.1) - 1(2.9) 1(2.9) 21(1.8) 46(4.0) * 40 1 8mg/kg 1. 60

(2)(DMARD) DMARD 3 ALTGPT ASTGOTDMARD 8 mg/kg+dmard 103/1582 (6.5%)+DMARD 18/1170 (1.5%) 8 mg/kg 6/288 (2.1%)MTX 14/284 (4.9%) (9) (3) 2.9 0.18.1 1.1 0.12.8 pjiasjia 3 2.9 1 MTX DMARDs 1.1 (4) in vitro IL-6 CYPs IL-6 CYPs IL-6 CYPs IL-6 CYP3A4CYP2C19 CYP2D6 IL-6 CYPs in vitro IL-6 CYP IL-6 CYP1A2CYP2CCYP2E1CYP3A mrna IL-6 CYP3A4 mrna IL-6 -naphthoflavone CYP1A1 CYP1A2 rifampicin CYP3A4 mrna CYP3A4 IL-6 rifampicin phenobarbital CYP3A4 61

CYP2B6CYP2C8CYP2C9 mrna in vitro IL-6 CYP3A4 mrna CYP2D6CYP1A2CYP2B6CYP2C9 CYP2C19 IL-6 IL-6 CYP IL-6 CYP IL-6 CYP CRP1.5mg/dL IL-6 CYP3A4 CYP2C19 (CYP3A4/CYP2D6 )CYP2C19 AUC 40% CYP3A4 CYPs CYPs TDM (5)gp130 gp130 IL-6 IL-6 IL-6 IL-6CT-1LIFIL-11CNTF gp130 KO gp130 conditional KO IL-6 gp130 KO conditional KO gp130 IL-6 IL-6 IL-6KO IL-6 62

(11) 6) IL-6 IL-6Cardiotropin1CT-1Leukemia Inhibitory FactorLIF IL-11Ciliary Neurotrophic FactorCNTFOncostatin MOSM (6) IL-6 IL-6 IL-6 1 6 IL-6 2 63

(mg/kg) Slc:ddY Slc:ddY Slc:ddY Slc:Wistar Slc:Hartley Slc:Hartley Beagle/CSK Slc:ddY Slc:SD a b250mm NaCl, 20mM, ph7.0 0 b, 1.33, 13.34, 133.4 3M 0 b, 1.33, 13.34, 133.4 8M 0 b, 1.33, 13.34, 133.4 78M 0 b, 1.33, 13.34, 133.4 8M in vitro 20, 67, 200 µg/ml 7M in vitro 200 µg/ml 7M 0 b, 66.7 4M 0 b, 133.4 1M, 2F 1, 10, 50 2 3M CPKCPK 3 0 b, 1.33, 13.34, 133.4 8M 0 b, 133.4 1M, 2F 0 c, 1.33, 13.34, 133.4 8M ph Na K Cl c175mm NaCl, 18mM, ph6.7 64

0, 6, 30, 150 mg/kg 0, 1, 10, 100 mg/kg (mg/kg) >150 >100 2 () 0, 2, 10, 50 mg/kg/ 1 2 () 0, 2, 10, 50 mg/kg/ 0, 0.4, 2, 10, 50 mg/kg/ (mg/kg) 10 1 0, 2, 10, 50 mg/kg/ 10 6 0, 1, 10, 100 mg/kg/ 100 0, 5, 16, 50 mg/kg/ 50 () 0, 5, 16, 50 mg/kg/ 0, 5, 50 mg/kg/ (mg/kg) 50 0, 0.5, 5, 50 mg/kg/ 50 0, 2, 10, 50 mg/kg/ 10 in vitro 0, 47.3, 96.4, 189, 379, 757 µg/plate in vitro 0, 47.3, 96.4, 189, 379, 757 µg/plate in vitro 0, 189.3, 378.5, 757 µg/ml 0.5 ml (30 mg/ml) 0.2 ml (30 mg/ml) 10µg/animal 1, 10 mg/kg 65

2 28 1 2 80 mg 1 200 mg1 400 mg1 2005 4 11 80 mg 2008 4 16 22000AMX01593 66

200 mg 2007 9 10 21900AMX01337 200 2005 4 11 21700AMZ00601 400 mg 2008 4 16 22000AMX01594 80 mg 2008 6 13 200 mg2007 12 21 2002005 6 3 400 mg2008 6 13 2008 4 16 200 mg 2008 4 16 200 mg 1 8 mg/kg 4 1 8mg/kg 2 1 2005 4 11 2015 4 10 10 2008 4 16 2014 2 15 5 10 67

80mg6399421A2026 200 mg6399421a1020 400 mg6399421a3022 68

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37Hirota H, et al.: Cell 189,1999 38Kopf M, et al.: Nature 339,1994 39 40 70

EU 5 2009 2 71

http//www.chugai-pharm.co.jp 72

ACT09 00106