(1) ) ) (2) (3) (4) (5) (1) (2) b (3)..

... -1... -1... -2... -6.... -1 (1)... -1 1)... -1 2)... -14 (2)... -19 (3)... -52 (4)... -18 (5)... -136.... -196 (1)... -196 (2) b... -224 (3)... -233.... -251.... -286.... -289 (1)... -289 (2)... -32 1)... -32 2)... -36 3)... -311 4)... -313 (3) Ca... -327 (4)... -336

RBC 1 4 /µl Hb g/dl Ht % Ret Plt 1 4 /µl WBC /µl Neu % Lympho % Mono % Eosino % Baso % MCV fl MCH pg MCHC % ph HCO 3 meq/l po 2 torr pco 2 torr P mg/dl Ca mg/dl Ca P mg/dl 2 TP g/dl Alb g/dl A/G / AST GOT IU/L ALT GPT IU/L LDH IU/L -GTP IU/L - ALP IU/L ALP % ALP U/L OC ng/ml T-Cho mg/dl LDL-Cho mg/dl HDL- Cho mg/dl TG mg/dl T-Bil mg/dl D-Bil mg/dl BUN mg/dl Cr mg/dl UA mg/dl Na meq/l K meq/l Cl meq/l Mg mg/dl i

Lp(a) mg/dl a RLP-Cho mg/dl intact-pth pg/ml HS-PTH pg/ml Fe µg/dl UIBC µg/dl TIBC µg/dl Cu µg/dl Zn µg/dl Al PICP ng/ml -C- ICTP ng/ml -C- PT % APTT % 1,25(OH) 2 D pg/ml 1,25- D 24,25(OH) 2 D ng/ml 24,25- D 25(OH)D ng/ml 25- D PK ng/ml MK-4 ng/ml -4 MK-7 ng/ml -7 HCG IU/L Kt/V PCR g/ 2 HPT ROD PTx NOS Not Otherwise Specified NEC Not Elsewhere Classified FAS Full Analysis Set PPS Per Protocol Set ITT Intent to Treat PC Protocol Compatible n Mean S.D. Standard Deviation S.E. Standard Error Min Minimum Max Maximum Median Range CI Confidence Interval SOC System Organ Class PT Preferred Term ii

. P P P P P P Al Ca Ca P PB-94 P P washout P P 6.mg/dL P 1 3 4 Ca P Ca P Ca 2 HPT P Ca Ca P P 4. 6.mg/dL Ca Ca 11.mg/dL Ca P P PTH intact-pth Ca 12 Electron Beam Tomography EBT 3-1

LDL-Cho B 12 1 /1 /2 D 25mg 475mg 44mg 43mg 4mg 8mg Ca in vitro P 1.5mm 9.mm -2

PB-94 P 38 6 1 1 1 1 2 1 3 2 Ca 4 5 1 6 24 6 48 1 b 2 3 3 1 3 a b c Ca 1 a Ca 5 2 P 593 535 535 334 21 19 86.2 3 PB-94 1.18 9.g 4.4g 325 535 7 5 24 592 24 48-3

b P P P P P P 1 PB-94 24 12 PB-94 17 8 96 PB-94 115 Ca 115 g/.5 4. 1 4.5 9. 1 3 1 3 1.5 7.5 1 3.67 9. 1 3.1 7. 1 3 36 1.71 9. 1 3 157 192 172 P PB-94 1 Ca 12 16 metoprolol enalapril warfarin digoxin 32 28 14 2.18 9. 1 3.68 9.12 1 3.93 11.63 1 3 6.5 1 3 4.3 1 3 PB-94 6.6 1 3 [N- 14 CH 3 ] PB-94 2.375 1 PB-94 2.418 metoprolol 1mg PB-94 2.418 enalapril 2mg PB-94 7.254 1 3 warfarin 3mg1 PB-94 7.254 1 3 digoxin 1mg1 1 7 2 6 8 8 48 4 4 44 8 52 32 1 1 2 2 4 14 4 14 24 16 15 1 1 1 1 1 3 4 5 6 6 1 2 3 29 3 31 32 33-4

a b c a 2 1 2 3 P P P P PB-94 18 6 PB-94 24 12 48 PB-94 37 Ca 38 PB-94 Ca 42 Ca PB-94 42 g/.95 4.75 1 2.85 14.25 1 3 1 3 1. 8.45 1 3 1 3.8 7.75 1 3.4 9. 1 3.4 7.2 1 3 PB-94 1.6 1.9 1 3 Ca.8 23.3 1 3 8 2 8 12 8 1 3 5 6 8-5

PB-94 P 25mg 1 1/6.5g 1.g 2.g 4.g 6 3 1 1.5g 3.g 1 3 7 1 PB-94 4.5g/ 8 4 2 PB-94 9.g/ 9 4 P 1.5g 3.g 3 P 1.5g 3.g P T-Cho LDL-Cho 94 4 3 washout 1.5 1. 2. 2.5g 1 3 6 P 1.5g/A -.94mg/dL 3.g/B -1.19mg/dL 6.g/C -2.24mg/dL 7.5g/D -2.84mg/dL P 8.mg/dL 3.g/ 8.mg/dL 6.g/ P 4mg/dL 6mg/dL Ca 94 62 66.% A 52.2% 12/23 B 64.% 16/25 C 68.2% 15/22 D 79.2% 19/24 T-Cho LDL-Cho ALP Cl Hb 6 3 D P 8.mg/dL 3.g/8.mg/dL 6.g/ P 4. 6.mg/dL 23 PB-94 115 Ca 115 3 washout PB-94 Ca 2 8 PB-94 3. 6.g/ Ca 3.g/ P Mean S.E.PB-94-6

5.62.9mg/dL Ca 5.59.9mg/dL P 95%CI -.22.29mg/dL P PB-94 Ca 1.mg/dL Ca PB-94 9.13.6mg/dL Ca 9.65.7mg/dL 95%CI -.7 -.34mg/dL Ca PB-94 Ca Ca Ca >11.mg/dL Kaplan-Meier Ca 16.8% PB-94 % Ca P PB-94 51.39.95 (mg/dl) 2 Ca 53.95.99 (mg/dl) 2 PB-94 Ca intact-pth PB-94 5.9g/ Ca 2.51g/ PB-94 7/115 6.9% Ca 46/115 4.% PB-94 4 34.8% Ca Ca 28 24.3% PB-94 7 Ca 5 Ca 4 1 T-Cho LDL-Cho PB-94 HDL-Cho ALP Cl Cu Zn D 1,25(OH) 2 D 25(OH)D 3.g/ 6.g/ P Ca P Ca Ca Ca 35 2 4 washout 2 8 3. 6.g/ P 5.93.16mg/dL 95%CI 5.61 6.26mg/dL -1.52.22mg/dL 95%CI -1.95-1.8mg/dL Ca 9.5mg/dL Ca P 56.14 1.55(mg/dL) 2-15.26 2.6(mg/dL) 2 intact-pth 5.4g/ 16/35 45.7% 8 22.9% 3 8.6% 2 5.7% T-Cho LDL-Cho Lp(a) RLP-Cho HDL-Cho ALP Cl D 1,25(OH) 2 D 25(OH)D E P P 157 1 4 48 P 6.mg/dL -7

48 5.63.1mg/dL Ca 9.mg/dL 48 9.33.8mg/dL Ca P 48 52.6 1.1(mg/dL) 2 intact-pth Median 48 184.pg/mL D Ca intact-pth 6pg/mL 36 3pg/mL 4.46g/113/157 72.% 72 45.9% 6 NOS NOS 1 2 1/157.6% T-Cho LDL-Cho TG HDL-Cho ALP Cl ph HCO 3 Ca P P 1.5mm 9.mm 2 2 P Mean S.D.3.g/-.3.33 95%CI -.68.626.g/-.2.46 95%CI -.95.9 b 44mg 172 P 2.64 3.96 5.28g 2 8 5.g/ P 136/168 81.% washout 5.5mg/dL T-Cho LDL-Cho Ca 44mg 43mg 192 1 2 4 4 44 5.g/ P Mean S.D. 8.66 2.21mg/dL 6.43 1.94mg/dL Ca T-Cho LDL-Cho HDL-Cho NOS Fe 1,25(OH) 2 D Ca 8mg 2 PB-94 Ca 52-8

P 5.2mg/dL Ca Ca Ca P PB-94 intact-pth PB-94 15~3pg/mL T-Cho LDL-Cho PB-94 Electron Beam Tomography EBT PB-94 Ca intact-pth PB-94 LDL-Cho P Ca 66.9% 2.3% NOS P -9

. (1) 1 2 PB-94 1) 1 PB-94 3 3 PB-94 1 1 2 6 2-1.92% 3 2 1 2 3 4 4 3 5 1 6 3 4mL 7 PB-94 25mg 4.5 1. 2. 4.g 1 4 PB-94 5 15 2mL 1 PB-94 6 3 2 PB-94 6 3 3 PB-94 6 3 4 PB-94 6 3 P Ca 4-1

3 5 PB-94 P Ca 5% 4 RBC Hb Ht Plt WBC WBC MCV MCH MCHC Ret TP Alb A/G AST ALT ALP ALP LDH-GTP TG T-Cho T-Bil D-Bil BUN UA Cr Na K Cl Ca P Fe UIBC PT APTT A D 25 OH DE K K 1 K 2 ph Cr BUN Na K Cl Ca P P Ca 5 24 48 72 P Ca 1 2 3 4 6 8 12 24 48 72 1 2 3 4 6 8 12 24 48 72 24 48 72 72 24 48 72 24 48 72 Na K Cl Ca P 2 4 8 12 24 48 72 24 48 72 72 24-11

1 1 4.6g/kg/ 1/6.5g 4 4.75g a 1 1.2g 4.g 2 3 2 1 36 P 2 12 1 2 PB-94 p=.47 2 P Ca P 2 4 12 1 1 UIBC 4.g -12

mg/dl 6 5 PB-94.5g プラセボ 4 3 2 1-1 11 12 24 23 35 36 48 47 6 59 72 71 (mg/dl) 6 5 ステップ 2 PB-94 1.g プラセボ 4 3 2 1-1 12 11 24 23 36 35 48 47 6 59 72 71 投与後時間 (mg/dl) 6 5 ステップ 3 PB-94 2.g プラセボ 4 3 2 1-1 11 12 24 23 35 36 47 48 59 6 71 72 投与後時間 (mg/dl) 6 5 ステップ 4 PB-94 4.g プラセボ 4 3 2 1-1 12 11 24 23 36 35 48 47 6 59 72 71 投与後時間 1 Mean S.D. -13

2) 2 PB-94 6 6 PB-94 1 1 2 6 2-1.92% 3 2 1 2 3 4 4 3 5 1 6 3 4mL 7 PB-94 25mg 2 1 1.5g 1 3.g 1 2 1 3 7 PB-94 5 15 2mL 2 1 1 PB-94 8 4 2 PB-94 9 4 P Ca 7 8 paired t-test PB-94 P Ca 5% -14

7 Cr BUN Na K Cl Ca P RBC Hb Ht Plt WBC WBC MCV MCH MCHC Ret TP Alb A/G AST ALT ALP ALP LDH-GTP TG T-Cho HDL-Cho LDL-Cho T-Bil D-Bil BUN UA Cr Na K Cl Ca P Mg Cu Zn Fe UIBCintact-PTH HS-PTH PT APTT A D 1,25(OH) 2 D 24,25(OH) 2 D 25(OH)DE K 1 B 12 ph P P Ca 8 P Ca 3 9: 9 9: 24 3 2 6 1 3 1 2 3 1 2 3 2 6 1 3 1 2 3 1 2 3 3 1 1 3 3 3 1 2 5 7 9 3 3 1 2 5 7 9 3 3 1 2 5 7 9 3 3 7 9 3 3 7 9 3 3 9: 9 9: 24-15

.5 1. 2. 4.g 1 9.g 1 1.5g 1 3 4.5g/ 1 3.g 1 3 9.g/ 7 24 2 1 Ret 3 1 25 P 1 p=.119 2 p=.166 P 2 1 p=.5 2 p=.24 1 2 3 P 3 t 1 p=.3 2 p<.1 9 9.g 4.5g t p=.3 Ca 1 p=.8 2 p=.879 P P P P P P 1 T-Cho 3 LDL-Cho 8 2 T-Cho 4 LDL-Cho 6 T-Cho LDL-Cho Ret -16

mg/ 12 1 1 PB-94 4.5g/ 日プラセボ P 8 6 4 2-4 -3-2 -2-1 -1 1 1 2 1 2 3 2 3 4 3 4 5 4 5 6 5 6 7 6 7 8 7 8 9 8 9 mg/ 12 1 2 PB-94 9.g/ 日プラセボ 8 P 6 4 2-4 -3-2 -2-1 -1 1 1 2 1 2 3 2 3 4 3 4 5 4 5 6 5 6 7 6 7 8 7 8 9 8 9 2P Mean S.D. mg 45 1 P 4 35 3 25 2 15 1 5 3 6 PB-94 4.5g/ 日プラセボ 9 mg 45 2 P 4 35 3 25 2 15 1 5 3 6 PB-94 9.g/ 日プラセボ 9 3 P Mean S.D. -17

.5 4.g 4.5 9.g/ 7 T-Cho LDL-Cho -18

(2) 3 PB-94 9 9 P PB-94 4 P 1 P washout 2 P 6. 1.mg/dL 1 2 75 2 3 3 1 P 4 P 3 5 D 1 6 2 1 washout P 1.mg/dL 2 3 4 5 6 3 3 3 AST ALT 1IU/L 7 8 3 9 HIV 1 PB-94 25mg 1 P 3 1st washout washout 2 PB-94 1 P 6. 1.mg/dL 1.mg/dL P 6. <8.mg/dL 8.<1.mg/dL * -19

9 2 2 A 4 B 8 C 1 D 1 3 6 P 3.mg/dL 2nd washout 2 2nd washout P A 1 2.5g1 3 1.5g/ B 1 41.g1 3 3.g/ C 1 82.g1 3 6.g/ D 1 1 2.5g1 3 7.5g/ 3 1 2 1st washout P 1.mg/dL 3 P 3.mg/dL 1.mg/dL 4 2nd washout P 1.mg/dL 5 6 7 8 1 1st washout 2nd washout P P 1 Ca Al Mg P 2 P 3P Ca Ca 2 3 D 1 1 4 RBC Hb Ht Plt WBC 1 P Ca 2 TP Alb AST ALT LDH ALP T-Cho LDL-Cho HDL-Cho T-Bil BUN Cr UA Na K Cl Mg intact-pth 3 Fe UIBC Cu ZnpH pco 2 po 2 HCO 3 PT APTT A B 12 D 1,25 OH 2 D 24,25 OH 2 D 25 OH D E K PK MK-4 MK-7 1-2

9 1 6 P P P P 4. 6.mg/dL P 4 1 2 3 4 2 1 P T-Cho LDL-Cho 5 2 5 1 2 3 4 5 1 25 1 2 b P 1 1.5g 3.g 6.g 7.5g P -1.7mg/dL -2.55mg/dL -3.78mg/dL -4.38mg/dL 1.86 1 5% 2 2% 5% 1 5.12g 2 1 5.72g 1 6.g 1.5g Tukey 8% 1 2 1 25 1 96 A 23 B 25 C 22 D 26 96-21

9 PPS 2 2 1 1 P Tukey =.5 1.5g/3.g/6.g/7.5g/ 4 5 =.5-3 -1 1 3-3 1 1 13.g/ -5-1 3 36.g/ -3-3 1 56.g/ -1-1 -1 37.5g/ 2 P Tukey =.5 P Tukey =.5 P Kaplan-Meier Log-rank =.5 2 1 F 95% 95%CI 2 4 * P P P 6mg/dL P 1mg/dL 8mg/dL -22

1 1st washout 2nd washout -3-2 -1 1 2 3 4 5 6 7 8 3 1 3 6 3 1 2 3 BUN 3 6 3 PT APTT 6 9.g/ 2 15.g/.4 11.6g/ b 2 4 Protocol Compatible PC 17 8 17 89 83.2% 7.g/ 17 83 77.6%8.37g/ 17 87 81.3% Intent to Treat ITT 168 8 168 136 81.%8.37g/ 168 132 78.6%7.g/ 168 127 75.6% 7.g/ 7.5g 5% 1.5g 1.5g 2 4 3.g 6.g b 2 7.g 8 77.6% 6 75.7% 4 63.6% 4 6 6 P washout 5.5mg/dL -23

1 96 4 11 96 1 1 94 94 A 23 B 25 C 22 D 24 FAS A 1 PPS 2 7% 1 A 1 B 3 C 3 D 3 FAS 93 A 22 B 25 C 22 D 24 PPS 83 A 21 B 22 C 19 D 21 96 A 23 B 25 C 22 D 26 94 A 23 B 25 C 22 D 24 2 A B C D 2 FAS 93 A 22 B 25 C 22 D 24 FAS 1 A1 B C D PPS 83 A 21 B 22 C 19 D 21 PPS 1 A1 B 3 C3 D 3 4-24

11 FAS PPS A B C D 1 a 2 b 1 7% c 2 1 1 2 d 1 1 2 3 a b c 2 3 3 5 13 d 2 PPS 12 12 n=83 A % n=21 B % n=22 C % n=19 D % n=21 % n=83 14 66.7 7 33.3 1 45.5 12 54.5 14 73.7 5 26.3 14 66.7 7 33.3 52 62.7 31 37.3 2 2 = 4.58 p=.255 3 4 4 5 5 6 6 7 7 75 65 65 2 9.5 1 4.8 1 47.6 7 33.3 1 4.8 19 9.5 2 9.5 1 4.5 4 18.2 7 31.8 9 4.9 1 4.5 18 81.8 4 18.2 4 21.1 11 57.9 4 21.1 17 89.5 2 1.5 3 14.3 3 14.3 8 38.1 6 28.6 1 4.8 19 9.5 2 9.5 6 7.2 12 14.5 36 43.4 26 31.3 3 3.6 73 88. 1 12. 2 2 2 = 9.419 p=.667 2 = 1.75 P=.783 Range Mean S.D. Median 31-72 55.8 1.1 57 39-74 56.9 9.3 58 48-69 55.6 6.5 55 31-73 53.7 1.8 55 31-74 55.5 9.3 56 F=.426 p=.735 kg 4 4 5 5 6 6 7 7 8 8 1 4.8 6 28.6 1 47.6 3 14.3 1 4.8 2 9.1 6 27.3 1 45.5 4 18.2 1 5.3 3 15.8 8 42.1 6 31.6 1 5.3 1 4.8 9 42.9 7 33.3 4 19. 5 6. 24 28.9 35 42.2 17 2.5 1 1.2 1 1.2 2 2 = 11.566 p=.712 Range Mean S.D. Median 36.1-75. 54.11 8.65 55.5 35.6-69.8 51.8 9.2 5.5 39.2-81.5 55.76 1.11 54. 36.-63.5 51.6 7.98 52.5 35.6-81.5 53.5 8.98 52.7 F= 1.221 p=.37 15 71.4 6 28.6 16 72.7 2 9.1 4 18.2 15 78.9 2 1.5 2 1.5 16 76.2 5 23.8 62 74.7 4 4.8 17 2.5 2 2 = 5.996 p=.424 2 HPT 21 1 13 61.9 5 23.8 11 52.4 22 1 14 63.6 9 4.9 8 36.4 19 1 13 68.4 4 21.1 15 78.9 21 1 15 71.4 2 9.5 14 66.7 83 1 55 66.3 2 24.1 48 57.8 9 42.9 12 57.1 7 31.8 15 68.2 12 63.2 7 36.8 7 33.3 14 66.7 35 42.2 48 57.8 2 2 = 5.75 p=.166-25

Ca meq/l P 6 6 12 12 36 36 6 6 12 12 24 24 Range Mean S.D. Median 3. 3. Ca Ca 12 n=83 A % n=21 6 28.6 1 4.8 3 14.3 7 33.3 4 19. 18.1-331.4 132.3 11.85 14.4 1 4.8 2 95.2 18 85.7 2 9.5 1 4.8 B % n=22 1 4.5 1 4.5 3 13.6 3 13.6 1 45.5 4 18.2 4.3-334.7 153.89 94.27 152.3 2 9.1 2 9.9 19 86.4 2 9.1 1 4.5 C % n=19 2 1.5 4 21.1 3 15.8 8 42.1 2 1.5 22.4-297.3 137.25 88.16 125.5 2 1.5 17 89.5 15 78.9 4 21.1 D % n=21 2 9.5 2 9.5 8 38.1 7 33.3 2 9.5 14.5-252.2 119.94 66.16 114.3 1 4.8 2 95.2 18 85.7 1 4.8 2 9.5 % n=83 1 1.2 1 1.2 1 12. 1 12. 17 2.5 32 38.6 12 14.5 4.3-334.7 135.96 87.96 133. 6 7.2 77 92.8 7 84.3 9 1.8 4 4.8 2 2 2 2 = 21.45 p=.257 F=.543 p=.654 2 =.83 p=.849 2 = p= 6.397.38 D 13 61.9 8 38.1 9 4.9 13 59.1 12 63.2 7 36.8 14 66.7 7 33.3 48 57.8 35 42.2 2 2 = 3.62 p=.36 5 23.8 6 27.3 5 26.3 5 23.8 21 25.3 5 23.8 5 22.7 3 15.8 4 19. 17 2.5 4 19. 4 18.2 4 21.1 4 19. 16 19.3 2 2 =.674 p= 1. 7 33.3 7 31.8 7 36.8 8 38.1 29 34.9 P mg/dl P mg/dl Ca mg/dl intact-pth pg/ml 6 8 8 1 Range Mean S.D. Median Range Mean S.D. Median Range Mean S.D. Median 11 52.4 1 47.6 5.9-11. 7.92 1.47 7.5 7.-1.7 8.83 1. 8.7 16-263 483 56 413 12 54.5 1 45.5 6.3-1.1 7.83 1.8 7.7 6.7-11.8 8.83 1.21 8.9 13-16 32 321 193 9 47.4 1 52.6 5.6-1.8 8.25 1.56 8.1 7.1-1.3 8.9.76 8.9 27-664 256 28 245 1 47.6 11 52.4 5.2-1.8 8.4 1.8 7.9 6.9-1. 8.86.76 8.9 77-113 44 336 281 42 5.6 41 49.4 5.2-11. 8. 1.29 7.8 6.7-11.8 8.86.94 8.9 13-263 363 384 251 2 2 =.318 p=.957 F=.395 p=.757 F=.22 p=.995 F= 1.463 p=.231-26

3 1 P P Mean S.E. P 5 13 1st washout P 5.4 5.7mg/dL 1st washout 7.8 8.3mg/dL P C D 1 2 P 4. 6.mg/dL 2nd washout P A -.94.3mg/dL B -1.19.2mg/dL C -2.24.4mg/dL D -2.84.25mg/dL 1. 9. A 群 (n=21~17) B 群 (n=22~16) C 群 (n=19~16) D 群 (n=21~16) 血清 P 濃度 (mg/dl) 8. 7. 6. 5. 4. -4-3 -2-1 1 2 3 4 5 6 +1 7 8+2 9 1st washout 2nd washout 5P Mean S.E. n 13 P mg/dl 1st washout t Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. t p A 21 5.57.26 1.17 7.92.32 1.47 6.98.26 1.18 -.94.3 1.39-3.19.6 B 22 5.42.22 1.2 7.83.23 1.8 6.64.28 1.33-1.19.2.95-5.867 <.1 C 19 5.7.29 1.27 8.25.36 1.56 6.1.4 1.72-2.24.4 1.73-5.664 <.1 D 21 5.65.29 1.34 8.4.24 1.8 5.21.27 1.22-2.84.25 1.14-11.396 <.1-27

P Mean S.E. P 6 =1.738 =79A -.94.29mg/dL B -1.19.28mg/dL C -2.24.3mg/dL D -2.83.29mg/dL Tukey A C D B D 14 mg/dl 2 1-1 -2-3 -4 A n=21 B n=22 C n=19 D n=21 6 P Mean S.E. 14 Tukey p A vs. B.927 A vs. C.14 A vs. D <.1 B vs. C.61 B vs. D <.1 C vs. D.486 P 5 C C p 15 15 p % p -3,-1,1,3 95.2 <.1 B -3,1,1,1 41.3 <.1 C -5,-1,3,3 81.7 <.1 C -3,-3,1,5 96.9 <.1 D -1,-1,-1,3 59.7 <.1-28

P 4. 6.mg/dL P 6.mg/dL 79 46 58.2% A 35.% 7/2 B 45.5% 1/22 C 7.6% 12/17 D 85.% 17/2 Kaplan-Meier 7Log-rank 2 =15.15 p=.2) % 1 9 8 7 6 5 4 3 2 1 D C B A 1 2 3 4 5 6 7 P P Mean S.E. P =.59 =79A -.17.5mg/dL B -.24.5mg/dL C -.39.6mg/dL D -.53.5mg/dL Tukey A C D B D 16 16 Tukey p A vs. B.788 A vs. C.27 A vs. D <.1 B vs. C.23 B vs. D.1 C vs. D.277-29

2 P 8.mg/dL 8.mg/dL P P P P 8 17 P 8.mg/dL 2 B 8.mg/dL C 6mg/dL D 2 Pmg/dL 1. 9. 8. 7. 6. 5. P8.mg/dL A 群 (n=12~9) B 群 (n=12~8) C 群 (n=9~7) D 群 (n=12~1) 4. -4-3 -2-1 1 2 3 4 5 6 +1 7 8+2 9 1st washout 2nd washout Pmg/dL 1. 9. 8. 7. 6. 5. P8.mg/dL A 群 (n=9~7) B 群 (n=1~8) C 群 (n=1~8) D 群 (n=9~6) 4. -4-3 -2-1 1 2 3 4 5 6 +1 7 8+2 9 1st washout 2nd washout 8P Mean S.E. -3

17 P mg/dl P 8.mg/dL n 1st washout t Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. t p A 12 5.49.28.97 6.83.17.58 6.43.28.95 -.41.39 1.34-1.56.314 B 12 4.95.18.62 7.3.14.49 5.8.32 1.11-1.23.35 1.21-3.51.5 C 9 5.6.32.95 6.91.29.86 5.37.48 1.44-1.54.39 1.18-3.926.4 D 12 5.61.39 1.35 7.38.21.74 4.84.33 1.15-2.53.29 1.1-8.687 <.1 P 8.mg/dL n 1st washout t Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. t p A 9 5.67.49 1.46 9.38.3.9 7.72.36 1.8-1.66.39 1.17-4.255.3 B 1 5.98.36 1.15 8.79.23.74 7.64.24.76-1.15.18.57-6.379 <.1 C 1 6.28.4 1.28 9.46.28.89 6.59.57 1.81-2.87.62 1.95-4.661.1 D 9 5.7.47 1.4 8.93.26.79 5.69.4 1.21-3.24.41 1.24-7.875 <.1 P P P 8.mg/dL 8.mg/dL 18Tukey P 8.mg/dL A D B D 8.mg/dL B C D 19 18 P mg/dl P 8.mg/dL =1.419 =41 P 8.mg/dL =1.77 =34 n Mean S.E. n Mean S.E. A 12 -.41.34 9-1.66.44 B 12-1.23.34 1-1.15.42 C 9-1.54.4 1-2.87.42 D 12-2.53.34 9-3.24.44 19 Tukey p P 8.mg/dL P 8.mg/dL A vs. B.348.841 A vs. C.151.213 A vs. D <.1.73 B vs. C.929.32 B vs. D.49.8 C vs. D.251.927-31

P 5 P 8.mg/dL C 8.mg/dL C p 8.mg/dL 8.mg/dL B 4 2 2 p P 8.mg/dL P 8.mg/dL % p % p (-3,-1,1,3) 95.3 <.1 68.3.2 B (-3,1,1,1) 58.3.2 14.4.141 C (-5,-1,3,3) 74. <.1 59.4.4 C (-3,-3,1,5) 84.6 <.1 85.2 <.1 D (-1,-1,-1,3) 68.6 <.1 44.9.12 P 4. 6.mg/dL P 21 P 8.mg/dL P 6.mg/dL 41 31 75.6% A 54.5% B 75.% C 85.7% D 9.9%8.mg/dL P 6.mg/dL 38 15 39.5% A 11.1% B 1.% C 6.% D 77.8% Kaplan-Meier 9Log-rank 8.mg/dL 2 =4.49 p=.2138.mg/dl 2 =18.64 p<.1 P 8.mg/dL 21 P 8.mg/dL n % n % A 11 6 54.5 5 9 1 11.1 8 B 12 9 75. 3 1 1 1. 9 C 7 6 85.7 1 1 6 6. 4 D 11 1 9.9 1 9 7 77.8 2 41 31 75.6 1 38 15 39.5 23-32

P 8.mg/dL % 1 D 9 C 8 B 7 6 A 5 4 3 2 1 1 2 3 4 5 6 % P 8.mg/dL 1 9 8 D 7 6 C 5 4 3 2 A 1 B 1 2 3 4 5 6 9 P 3 Ca Mean S.E. Ca 1 22 1st washout Ca 9.5 9.8mg/dL 1st washout 8.8 8.9mg/dL Ca 9.mg/dL Ca 8.9 9.2mg/dL A.1.9mg/dL B.11.11mg/dL C.25.15mg/dL D.12.8mg/dL -33

血清 Ca 濃度 (mg/dl) 11. 1.5 1. 9.5 9. 8.5 8. A 群 (n=21~17) B 群 (n=22~16) C 群 (n=19~16) D 群 (n=21~16) -4-3 -2-1 1 2 3 4 5 6 +1 7 +2 8 9 1st washout 2nd washout 1 Ca Mean S.E. n 22 Ca mg/dl 1st washout t Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. t p A 21 9.47.2.93 8.83.22 1. 8.85.18.84.1.9.43.154.879 B 22 9.75.35 1.64 8.83.26 1.21 8.95.25 1.16.11.11.54.995.331 C 19 9.67.25 1.7 8.9.18.76 9.15.18.79.25.15.64 1.683.11 D 21 9.5.15.68 8.86.17.76 8.99.14.65.12.8.39 1.475.156 4 Ca P Ca P 11 23 1st washout Ca P 52 55 mg/dl 2 1st washout 69 74 mg/dl 2 Ca P 47 62 mg/dl 2 C D 1st washout Ca P 積 (mg/dl) 2 8 75 7 65 6 55 5 45 4 A 群 (n=21~17) B 群 (n=22~16) C 群 (n=19~16) D 群 (n=21~16) -4-3 -2-1 1 2 3 4 5 6 +1 7 8+2 9 1st washout 2nd washout 11 Ca P Mean S.E. -34

n 23 Ca P mg/dl 2 1st washout t Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. Mean S.E. S.D. t p A 21 52.41 2.37 1.84 7.5 3.99 18.3 61.93 2.76 12.63-8.56 3.11 14.24-2.756.12 B 22 53. 3.1 14.13 68.6 2.16 1.15 58.99 2.71 12.7-9.61 2.12 9.95-4.531 <.1 C 19 55.3 3.46 15.7 73.57 3.57 15.55 55.8 3.69 16.8-18.49 3.41 14.87-5.422 <.1 D 21 53.52 2.79 12.8 71.13 2.27 1.41 46.77 2.57 11.79-24.36 2.36 1.81-1.331 <.1 5 intact-pth Median intact-pth 24 intact-pth 1st washout B 24 intact-pth pg/ml n 1st washout A 21 B 22 C 19 D 21 183. 99, 447 94. 25, 445 134. 42, 2 211. 18, 342 413. 136, 597 193. 59, 455 245. 59, 339 281. 164, 48 39. 29, 546 136.5 65, 388 17. 46, 243 265. 98, 462 3. -23, 31-2.5-7, 6-46. -126, -15-66. -99, -6 Wilcoxon u p.556.578 2.78.38 2.636.8 2.27.27 Median 25%,75% 6 25 A 19.% 4/21 B 36.4% 8/22 C 57.9% 11/19 D 71.4% 15/21 Tukey Steel-Dwass A C D B D 26 25 95%CI 1 3 6 11 A 4.8 14.3 28.6 52.4 5.4-41.9 21 4.8 19. 47.6 1. 4 4 7 7 B 18.2 18.2 31.8 31.8 17.2-59.3 22 18.2 36.4 68.2 1. 6 5 5 3 C 31.6 26.3 26.3 15.8 33.5-79.7 19 31.6 57.9 84.2 1. 11 4 5 1 D 52.4 19. 23.8 4.8 47.8-88.7 21 <52.4> 71.4 95.2 1. % % -35

26 Tukey Tukey p A vs. B -2.99.447 A vs. C -4.7.24 A vs. D -5.896 <.1 B vs. C -2.6.488 B vs. D -3.864.32 C vs. D -1.739.68 7 T-Cho LDL-Cho HDL-Cho 27 T-Cho LDL-Cho HDL-Cho B T-Cho mg/dl LDL-Cho mg/dl HDL-Cho mg/dl 27 1st washout t A 23 178. 53.8 182.5 55.6 16.9 43.1-21.6 22.3-4.643 <.1 B 25 163.9 48.3 175.6 48.4 14.8 4.9-34.8 2. -8.675 <.1 C 22 178.3 33.1 181.9 32.4 151.2 28.3-3.7 16.4-8.798 <.1 D 24 179.6 36.2 182.2 32.6 143.3 35.4-38.9 24.5-7.785 <.1 A 23 11.8 41.5 17.5 43.2 87.1 29.1-2.3 23.4-4.171 <.1 B 25 91.9 38.4 11.4 36.9 66.9 3.2-34.5 17.5-9.841 <.1 C 22 16.6 34.8 11.8 29.8 79.4 24.9-31.4 13.6-1.798 <.1 D 24 12. 28. 16.3 24.5 65.8 2.9-41.3 19.1-1.397 <.1 A 23 47. 13.4 44. 14. 46.3 14.5 2.3 6.7 1.65.113 B 25 48.9 14.7 46.4 13. 5.8 15.4 4.4 6.1 3.597.1 C 22 47.4 15.4 45. 14.6 49. 15.7 4. 6.7 2.817.1 D 24 51.6 16.8 49.9 14.8 55.3 18.5 5.4 6.5 4.43.1 Mean S.D. t p 4Kt/V PCR 6 3 28 Kt/V PCR 29 B C D Kt/V B Kt/V PCR R-1-36

n 28 1st washout t n 6 N t p A 11 83.7 61.8 11 884.2 93.4 11 53.5 54.8.976.352 B 14 811.2 68.1 11 79.6 75.3 11-68.8 2.3-3.391.7 C 12 811.8 47.5 12 758.8 52.9 12-53. 51.1-1.37.322 mg D 14 84.1 63.4 1 781.3 9.7 1-6.4 55.2 -.116.91 51 813.6 3. 44 83.2 38.4 44-19.7 24.1 -.82.417 A 11 355.9 42.4 11 381.5 38.8 11 25.6 31.3.819.432 B 14 342.1 46.7 11 38.1 62.1 11 13.5 21.6.623.547 C 12 349.8 31. 12 33. 26.5 12-19.8 28.9 -.686.57 mg D 14 374.6 4.9 1 364.4 53. 1-2.5 36.3 -.7.946 51 355.8 2.2 44 363.2 22.5 44 3.8 14.6.261.796 A 11 1993. 121.2 11 254.6 127.4 11 61.5 67..918.38 B 14 1778.6 86.6 11 1644.9 15. 11-217.8 71.4-3.49.12 C 12 1793.2 89.6 12 1631.7 91.7 12-161.5 71.1-2.272.44 kcal D 14 1722.4 98.8 1 1542.3 119. 1-156.1 8.6-1.936.85 51 1812.8 49.7 44 172.4 61.2 44-118.6 38.5-3.78.4 A 11 67.1 4.5 11 71.9 7.2 11 4.8 4.7 1.18.333 B 14 64.7 4.1 11 61.1 4.3 11-7.3 2. -3.673.4 C 12 62.5 3.4 12 6.6 3.8 12-1.9 4.1 -.453.659 g D 14 64.3 4.6 1 58.8 6.2 1-5.9 4.5-1.299.226 51 64.6 2.1 44 63.1 2.7 44-2.5 2. -1.27.234 A 11 59.2 5.3 11 63.1 6.5 11 3.8 6.3.618.551 B 14 55. 3.5 11 47.4 5.6 11-9.2 4.1-2.264.47 C 12 55.4 2.8 12 53.6 3.3 12-1.8 2.5 -.72.487 g D 14 55.7 4.6 1 42.4 4.1 1-11.8 4.7-2.55.34 51 56.2 2. 44 51.9 2.7 44-4.5 2.4-1.93.64 A 11 7754.5 181. 11 7763.6 1284.6 11 9.1 751.8.12.991 B 14 676.7 442.7 11 7675.8 843.7 11 51.5 657.7.763.463 C 12 6618.1 637.6 12 6644.4 75.7 12 26.4 443.3.6.954 mg D 14 82. 733.8 1 7193.3 181.5 1-137. 791.5-1.731.118 51 7336.6 364.6 44 736.8 482.3 44-176.6 334.9 -.527.61 A 11 2115.8 145.5 11 26.3 168.1 11-19.5 91.3-1.199.258 B 14 263.7 176.8 11 2163.4 245.4 11-51.7 161.2 -.321.755 C 12 265.8 119.4 12 1851.8 144.8 12-214.1 139.6-1.533.154 mg D 14 2168.4 193.9 1 2316.7 435.6 1 232.7 388.3.599.564 51 214.2 81.3 44 274. 127.8 44-45.8 15.5 -.434.667 A 11 348.8 425. 11 352.4 55.1 11 3.6 295.6.12.991 B 14 2658.1 174. 11 317.8 331.7 11 197.2 258.6.763.463 C 12 262. 25.7 12 2612.3 277.5 12 1.4 174.3.6.954 mg D 14 3223.9 288.5 1 2828.1 425.2 1-538.6 311.2-1.731.118 51 2884.5 143.4 44 2872.8 189.6 44-69.4 131.7 -.527.61 Mean S.E. -37

29 Kt/V PCR 1st washout t n n n n n 6 t p A 23 1.43.5 23 1.39.5 17 1.38.5 18 1.38.5 18.1.2.343.736 B 25 1.53.6 24 1.5.6 16 1.54.8 18 1.52.7 17.6.2 3.93.7 Kt/V C 22 1.41.4 21 1.4.4 17 1.42.5 18 1.4.5 18 -.1.2 -.288.777 D 23 1.46.5 24 1.43.5 17 1.41.6 18 1.41.6 18 -.1.2 -.297.77 93 1.46.3 92 1.43.3 67 1.44.3 72 1.43.3 71.1.1 1.18.242 A 23 1.2.3 23 1.2.3 17 1.2.3 18 1.1.3 18.1.3.424.677 PCR g/ 5 B 25 1.6.3 24 1.5.4 16 1.6.4 18 1.5.4 17.3.3 1.176.257 C 22 1.3.3 21 1..3 17.97.4 18.98.4 18 -.1.3 -.19.852 D 23 1.3.4 24 1.3.3 17.97.4 18.96.4 18 -.8.3-2.678.16 93 1.4.2 92 1.3.2 67 1.1.2 72 1..2 71 -.1.1 -.696.488 Mean S.E. 1 3 31 94 A 23 B 25 C 22 D 24 A 21 91.3% 52 B 23 92.% 88 C 2 9.9% 67 D 23 95.8% 91 A 7 3.4% 7 B 15 6.% 25 C 13 59.1% 18 D 19 79.2% 38 A 12 52.2% 13 B 16 64.% 36 C 15 68.2% 32 D 19 79.2% 46 D A 7 5 1 B 28 7 1 C 14 15 3 D 11 26 9 A 4 17.4%B 5 2.%C 9 4.9%D 12 5.% A.%B 3 12.%C 4 18.2%D 7 29.2% NOS A.%B 3 12.%C 1 4.5%D 5 2.8% Cochran-Armitage Z = -2.844 p =.2 Z = -2.776 p =.3 A 1 NOSB 1 C 2 NOS NOS D 4 NOS NOS C- 8-38

MedDRA SOC MedDRA PT 3 % * A B 5 4 3 5,4,3 2,1 5 4 3 5,4,3 2,1 1 (4.) 1 (4.) NOS 1 (4.) 1 (4.) NOS 1 (4.3) 1 (4.3) 1 (4.3) 2 (8.) 1 (4.) NOS 1 (4.3) 1 (4.3) 1 (4.3) 1 (4.3) 1 (4.) 1 (4.3) 2 (8.7) 1 (4.3) NEC 1 (4.3) 1 (4.3) 3 (12.) NOS 1 (4.) NEC 1 (4.) NEC 1 (4.) NOS 1 (4.3) 1 (4.3) 5 (21.7) 6 (26.1) 1 (4.3) 2 (8.) 7 (28.) 3 (12.) 12 (48.) 3 (12.) 1(4.) 1 (4.) 1 (4.) 3 (12.) NOS 1 (4.) 2 (8.) 3 (12.) 1 (4.3) 1 (4.3) 2 (8.7) 2(8.) 3 (12.) 5 (2.) 1 (4.) NOS 1 (4.3) 1 (4.3) 2 (8.) 1 (4.3) 1 (4.3) 1 (4.) 1 (4.) NOS 1 (4.) 1 (4.) 2 (8.) 2 (8.) 1 (4.) 1 (4.) 1 (4.3) 2 (8.) NOS 2 (8.) 2 (8.) 2 (8.) 2 (8.7) 2 (8.7) 2 (8.7) 2 (8.) 2 (8.) 1 (4.3) 1 (4.3) NOS 1 (4.3) 1 (4.3) 9 (39.1) 12 (48.) NOS 1 (4.) NOS 1 (4.3) 7 (3.4) 12 (48.) NOS 1 (4.3) NOS 1 (4.) NOS 1 (4.3) NOS 1 (4.3) 2 (8.) NOS 1 (4.3) 1 (4.) 1 (4.) 1 (4.3) 1 (4.3) 5 (21.7) 1 (4.) 3 (12.) 4 (16.) 5 (2.) 1 (4.) 1 (4.) 1 (4.3) 1 (4.3) NOS 1 (4.) 1 (4.) 2 (8.) 1 (4.) 5 4 32 1-39

MedDRA SOC MedDRA PT 3 % * C D 5 4 3 5,4,3 2,1 5 4 3 5,4,3 2,1 1 (4.5) 1 (4.5) NOS NOS 1 (4.5) 1 (4.5) 1 (4.2) NOS 1 (4.2) NEC 1 (4.2) NOS NEC NEC 1 (4.2) NOS 4 (18.2) 8 (36.4) 1 (4.5) 13 (59.1) 5 (2.8) 9 (37.5) 4 (16.7) 18 (75.) 1 (4.2) 2 (9.1) 2 (9.1) 4 (18.2) 2 (8.3) 5 (2.8) 7 (29.2) NOS 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 2 (9.1) 1 (4.2) 1 (4.2) 1 (4.5) 4 (18.2) 1 (4.5) 6 (27.3) 3 (12.5) 4 (16.7) 1 (4.2) 8 (33.3) NOS 1 (4.5) 1 (4.2) 1 (4.2) 2 (8.3) 1 (4.2) 2 (8.3) 2 (8.3) 1 (4.2) 1 (4.2) NOS 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 2 (8.3) 1 (4.2) 3 (12.5) 2 (8.3) NOS 2 (8.3) 2 (8.3) 2 (8.3) 2 (9.1) 1 (4.5) 3 (13.6) 2 (8.3) 1 (4.2) 1 (4.2) 4 (16.7) 4 (18.2) 1 (4.2) 1 (4.2) 2 (8.3) 1 (4.2) 1 (4.5) 1 (4.2) 1 (4.2) NOS 2 (9.1) 1 (4.5) 1 (4.2) 1 (4.2) 11 (5.) 13 (54.2) NOS 1 (4.2) NOS 1 (4.5) 1 (45.5) 12 (5.) NOS NOS NOS 1 (4.5) NOS 1 (4.5) 1 (4.2) 1 (4.5) NOS 1 (4.5) 2 (9.1) 2 (9.1) 4 (18.2) 2 (8.3) 2 (8.3) 4 (16.7) 5 (2.8) 1 (4.2) 1 (4.2) NOS 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.2) 5 4 32 1-4

MedDRA SOC MedDRA PT 3 % * A B 5 4 3 5,4,3 2,1 5 4 3 5,4,3 2,1 1 (4.) 1 (4.) 1 (4.) 1 (4.) ph 1 (4.3) 1 (4.3) 2 (8.) 3 (13.) 2 (8.) C- po2 1 (4.) 1 (4.) 1 (4.3) 1 (4.) 1 (4.) 1 (4.3) 3 (13.) 3 (13.) 4 (16.) 4 (16.) 1 (4.) 1 (4.) A 1 (4.3) 1 (4.3) NOS 1 (4.3) 1 (4.3) 2 (8.) 2 (8.) 1 (4.) 1 (4.) K 1 (4.3) 1 (4.3) 2 (8.) 2 (8.) 1 (4.3) 1 (4.3) 4 (17.4) 1 (4.) 1 (4.) 6 (24.) 1 (4.3) 1 (4.3) 2 (8.7) 1 (4.) 1 (4.) 4 (16.) 1 (4.) 1 (4.) 1 (4.3) 2 (8.) 1 (4.3) 1 (4.) 2 (8.7) 4 (16.) 1 (4.) 1 (4.3) NOS 1 (4.3) 3 (12.) NEC 1 (4.) 1 (4.) 1 (4.3) 1 (4.) 1 (4.3) 1 (4.) NOS 1 (4.3) 1 (4.3) 4 (17.4) 1 (4.) 1 (4.) 2 (8.) 1 (4.3) NOS 1 (4.) 1 (4.) 1 (4.) 1 (4.) 1 (4.) NOS 1 (4.3) 1 (4.3) 3 (13.) 1 (4.) 1 (4.) 1 (4.) NOS NOS 5 4 32 1-41

MedDRA SOC MedDRA PT 3 C % * 5 4 3 5,4,3 2,1 5 4 3 5,4,3 2,1 1 (4.2) 2 (8.3) 2 (8.3) ph 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 2 (8.3) 1 (4.2) 1 (4.5) 1 (4.5) C- 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) po2 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 3 (13.6) 3 (13.6) 1 (4.5) 1 (4.2) 2 (8.3) 3 (12.5) 6 (25.) 1 (4.5) 1 (4.2) 2 (8.3) 3 (12.5) A 1 (4.5) 1 (4.5) NOS 2 (9.1) 2 (9.1) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.2) K 2 (8.3) 2 (8.3) 1 (4.5) 1 (4.5) 4 (18.2) 2 (8.3) 1 (4.5) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 2 (9.1) 3 (12.5) 1 (4.5) NOS 1 (4.2) 1 (4.5) NEC 1 (4.5) 1 (4.5) 2 (8.3) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.5) NOS 1 (4.2) 1 (4.5) 1 (4.5) 3 (13.6) 1 (4.2) 1 (4.2) 3 (12.5) NOS 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.2) 1 (4.5) NOS NOS 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 2 (8.3) 1 (4.2) NOS 1 (4.2) 5 4 32 1 D -42

31 % * MeDRA SOC MeDRA PT A n=23) B (n=25) 7 5 1 13 28 7 1 36 1 (4.) 1 (4.) NOS 1 (4.) 1 (4.) NOS 1 (4.3) 1 (4.3) NOS 1 (4.3) 1 (4.3) 2 (8.7) 3 (13.) 1 (4.3) 6 (26.1) 7 (28.) 4 (16.) 1 (4.) 12 (48.) 2 (8.) 1 (4.) 3 (12.) NOS 3 (12.) 3 (12.) 2 (8.7) 2 (8.7) 4 (16.) 1 (4.) 5 (2.) NOS 1 (4.3) 1 (4.3) 1 (4.3) 1 (4.3) 1 (4.) 1 (4.) NOS 1 (4.) 1 (4.) 2 (8.) 2 (8.) 1 (4.) 1 (4.) NOS 2 (8.) 2 (8.) 1 (4.3) 1 (4.3) 2 (8.7) 1 (4.3) 1 (4.3) 4 (16.) 4 (16.) 1 (4.) 1 (4.) NOS 2 (8.) 2 (8.) 1 (4.) 1 (4.) 1 (4.) 1 (4.) ph 1 (4.3) 1 (4.3) C- po 2 1 (4.) 1 (4.) 1 (4.) 1 (4.) 3 (13.) 3 (13.) 4 (16.) 4 (16.) 1 (4.) 1 (4.) A 1 (4.3) 1 (4.3) NOS 1 (4.3) 1 (4.3) 2 (8.) 2 (8.) 1 (4.) 1 (4.) K 1 (4.3) 1 (4.3) 2 (8.) 2 (8.) 1 (4.3) 1 (4.3) 1 (4.) 1 (4.) 1 (4.3) 1 (4.3) 1 (4.) 1 (4.) NEC 1 (4.3) 1 (4.3) 1 (4.) 1 (4.) NOS 1 (4.) 1 (4.) 1 (4.) 1 (4.) NOS 1 (4.3) 1 (4.3) 1 (4.) 1 (4.) NOS *: -43

MeDRA SOC 31 % MeDRA PT * C n=22 D n=24 14 15 3 32 11 26 9 46 1 (4.5) 1 (4.5) NOS NOS 1 (4.5) 1 (4.5) NOS 4 (18.2) 8 (36.4) 1 (4.5) 13 (59.1) 3 (12.5) 12 (5.) 3 (12.5) 18 (75.) 1 (4.5) 2 (9.1) 1 (4.5) 4 (18.2) 6 (25.) 1 (4.2) 7 (29.2) NOS 1 (4.2) 1 (4.2) 2 (9.1) 2 (9.1) 1 (4.2) 1 (4.2) 1 (4.5) 5 (22.7) 6 (27.3) 2 (8.3) 5 (2.8) 1 (4.2) 8 (33.3) NOS 2 (8.3) 2 (8.3) 1 (4.2) 1 (4.2) 2 (8.3) 1 (4.2) 1 (4.2) NOS 1 (4.5) 1 (4.5) 2 (8.3) 1 (4.2) 3 (12.5) NOS 2 (8.3) 2 (8.3) 1 (4.5) 2 (9.1) 3 (13.6) 3 (12.5) 1 (4.2) 4 (16.7) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.2) 3 (13.6) 1 (4.5) 4 (18.2) 3 (12.5) 1 (4.2) 4 (16.7) 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) NOS 1 (4.5) 1 (4.5) 2 (8.3) 2 (8.3) ph 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) C- 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) po 2 1 (4.2) 1 (4.2) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 3 (13.6) 3 (13.6) 3 (12.5) 2 (8.3) 1 (4.2) 6 (25.) 2 (8.3) 1 (4.2) 3 (12.5) A 1 (4.5) 1 (4.5) NOS 2 (9.1) 2 (9.1) 1 (4.2) 1 (4.2) 1 (4.2) 1 (4.2) K 2 (8.3) 2 (8.3) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) NEC 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) NOS 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) NOS NOS 1 (4.5) 1 (4.5) 1 (4.2) 1 (4.2) *: -44

2 A 1 B 1 D 2 4 1st washout 1 3 2nd washout A 1 B 1 NOS 2 3 Hb ALP Cl Hb B ALP Cl C 32 n mmhg mmhg kg kg RBC 1 4 /µl Hb g/dl 1st washout 32 t t p f,p A 23 161.1 3.5 157.1 3.2 158.5 31.1 1.4 2.1.332.743 B 25 15.5 23. 15.8 22.2 154.4 21.6 3.6 2.4.881.387.8 C 22 151.5 26.6 145.5 21. 15.2 2.2 4.6 16.4 1.327.199.999 D 24 146.5 21.9 141.1 22.3 147.4 19.2 6.3 17.1 1.85.84 A 23 82. 15. 83. 15.4 83.1 15.3.1 11..38.97 B 25 83.3 14.3 85.2 14.4 83. 14.3-2.2 11.2 -.981.336.65 C 22 85. 13.1 77.9 12. 81.7 11.9 3.8 11.1 1.617.121.613 D 24 81.5 12.6 78.8 12.5 81.9 12.8 3.1 1.8 1.43.174 A 23 56.24 8.8 56.39 8.89 56.33 8.72 -.7.78 -.399.693 B 25 53.9 8.86 53.17 8.79 53.4 8.78 -.14.8 -.846.46.75 C 22 58.96 1.2 59.15 1.13 59.1 1.14 -.15.66-1.37.312.973 D 24 53.7 8.4 53.73 7.96 53.68 8.1 -.6.82 -.349.73 A 23 53.67 8.47 53.81 8.53 53.71 8.32 -.1.39-1.246.226 B 25 49.66 7.85 5.58 8.66 49.6 7.71 -.17.46-1.811.83 2.55 C 22 56.14 9.72 56.25 9.71 56.24 9.71 -.1.32 -.132.896.64 D 24 51.13 7.92 51.25 7.78 51.36 7.83.11.43 1.277.214 A 23 326.7 49.7 319.5 43.2 325.7 43. -1.8 25. -.323.75 B 25 319.6 37.8 312.8 36.6 32.8 32.6-1. 18.1-2.766.11 1.919 C 22 336.3 47.3 331.7 5.2 32.1 49. -11.5 12. -4.524 <.1.132 D 24 337.5 42.9 331.9 43.6 316.1 39.9-15.8 18.5-4.175 <.1 A 23 9.78 1.13 9.83 1.7 9.87.98.3.73.18.859 B 25 9.92.95 9.73.99 9.46.91 -.27.52-2.64.14 3.664 C 22 1.4 1.24 1.21 1.32 9.86 1.3 -.34.43-3.695.1.15 D 24 1.35.99 1.18.98 9.59.88 -.59.65-4.435 <.1 Mean S.D. -45

32 n 1st washout t t p f,p A 23 3.68 3.58 3.71 3.35 3.9 2.87.7 2.42.126.91 Ht B 25 3.98 2.92 3.32 3.5 29.46 2.55 -.86 1.73-2.475.21 2.184 % C 22 32.24 4.6 31.7 4.3 3.82 4.27 -.88 1.24-3.339.3.96 D 24 32.38 3.6 31.75 3.55 3.35 3.13-1.4 1.95-3.52.2 A 23 18.99 5.78 2.28 6.4 19.83 5.5 -.75 2.14-1.6.125 Plt B 25 16.2 6.47 16.79 6.25 16.31 6.48 -.48 1.88-1.28.213 1.582 1 4 /µl C 22 18.16 4.45 17.91 4.5 18.4 4.78.49 1.99 1.158.26.199 D 24 19.5 3.34 18.99 3.4 18.3 3.49 -.95 2.9-1.614.12 A 23 6252.2 1746.7 6352.4 272.6 6173.9 1746.7-219. 1346.3 -.746.465 WBC B 25 584. 1356.9 572. 1461.2 564. 1564.8-116. 84. -.721.478.58 /µl C 22 5772.7 1188.5 5459.1 1168.1 5468.2 1396.7 9.1 134.2.32.975.982 D 24 59. 1337.7 5887.5 1678.3 5691.7 1366. -195.8 1263.7 -.759.455 A 23 3.95.26 3.87.29 3.88.3..16.127.9 Alb B 25 3.87.31 3.8.28 3.85.3.5.26.923.365.378 g/dl C 22 3.92.23 3.8.22 3.86.26.6.26 1.168.256.769 D 24 3.93.34 3.88.29 3.85.32 -.3.29 -.499.623 A 23 6.73.54 6.7.43 6.6.41 -.1.28-1.746.95 TP B 25 6.44.48 6.4.44 6.41.45.1.28.213.833.374 g/dl C 22 6.66.51 6.59.45 6.52.4 -.7.31-1.39.31.772 D 24 6.63.48 6.62.52 6.5.52 -.13.32-1.926.67 A 23 14.4 5.6 14.6 6.8 16. 8.2 1.3 5.6 1.148.263 AST B 25 14.8 7.5 13.8 7.5 14.2 7.6.3 2.6.621.541.936 IU/L C 22 12.1 5.1 12.7 5.5 14.5 5.8 1.8 5.2 1.632.118.427 D 24 1.3 4.5 1.3 3.8 13.3 5.2 3.1 4.6 3.37.3 A 23 12.1 8. 12.4 6.8 14.2 8.7 1.7 7.1 1.169.255 ALT B 25 11.6 7.4 11.4 6.7 11. 6.7 -.5 3.3 -.723.476 1.739 IU/L C 22 1.9 5.1 1.8 4.9 13. 8.2 2.2 5.5 1.872.75.165 D 24 9.8 5. 1.5 7. 14. 11.3 3.5 7.8 2.196.38 A 23 364.2 84. 369.7 88.6 36.6 98.4-9. 41.3-1.5.35 LDH B 25 347.5 66.4 351.6 76. 347.9 72.3-3.7 37.3 -.494.626.37 IU/L C 22 345.5 9.8 385.4 166.4 364.6 95.7-2.8 183.7 -.53.61.99 D 24 316.7 79.6 323.8 83.3 334.1 76.3 1.3 36.6 1.373.183 A 23 259.3 43.1 261.1 412.8 265.3 366.1 4.1 55.4.358.724 ALP B 25 197.3 17.6 193.6 91.5 24.2 92.5 1.6 34.3 1.546.135 5.872 IU/L C 22 157.4 45.1 152.5 46.3 175.6 49.3 23.2 28.1 3.868.1.1 D 24 185.8 95.7 18.5 83.9 232.1 115.6 51.6 49.2 5.134 <.1 A 23.23.1.19.6.2.8.1.8.826.418 T-Bil B 25.21.9.22.8.22.9 -.1.7 -.569.574.57 mg/dl C 22.19.6.24.17.23.1 -.1.2 -.216.831.636 D 24.21.6.21.8.19.6 -.2.7-1.163.257 A 23 77.3 12.7 78.5 11.6 75.4 13.3-3.1 12.9-1.141.266 BUN mg/dl B 25 78.9 12.6 78.3 16. 75.4 14.7-3. 12.8-1.155.259 2.195 C 22 77.7 12.6 75. 12.9 73.5 13.9-1.5 11.6 -.61.549.94 D 24 76.8 14.1 77.5 11.5 68.2 14. -9.3 9.9-4.596 <.1 Mean S.D. -46

32 n 1st washout t t p f,p A 23 24.3 6.1 25.5 6.2 24.5 6.8-1. 4.2-1.181.25 BUN B 25 23.4 6.7 22.3 7.9 22.6 7.4.3 5.4.249.85.747 mg/dl C 22 24.8 6.2 24. 5.5 23.7 6.2 -.4 5. -.334.742.527 D 23 22.5 6.8 24. 4.6 22.2 6.5-1.9 3.6-2.57.2 A 23 13.11 2.17 12.85 2.49 12.81 2.44 -.4 1.5 -.131.897 Cr B 25 11.92 1.83 11.9 1.93 11.41 2.26 -.49 1.7-2.289.31 1.794 mg/dl C 22 13.59 1.95 13.47 1.98 13.33 2.6 -.14.85 -.77.45.154 D 24 13.8 1.87 13.31 1.85 12.63 2.2 -.68.89-3.743.1 A 23 8.5 1.2 8.2.98 7.73 1.5 -.47.75-3.11.6 UA B 25 8.1 1.7 7.79 1.1 7.33 1.22 -.46 1.1-2.18.46 1.992 mg/dl C 22 8.66 1.34 8.34 1.2 7.73 1.12 -.61 1.12-2.548.19.121 D 23 8.56 1.26 8.62 1.45 7.4 1.34-1.25 1.1-5.468 <.1 A 23 139.8 2.6 14.3 2.3 14. 2. -.3 2.2 -.65.522 Na B 25 139.1 3.6 139.5 2.5 138.9 3.9 -.6 2.9-1.19.318.535 meq/l C 22 139.4 2.7 139.5 2.3 139.1 2.3 -.5 2.3 -.917.369.66 D 24 137.9 3.3 139.8 2.4 138.8 2.8-1. 2.5-1.972.61 A 23 5.31.55 5.39.69 5.7.38 -.32.74-2.6.51 K B 25 5.28.6 5.42.81 5.26.72 -.16.73-1.119.274.61 meq/l C 22 5.26.62 5.16.86 5.8.62 -.9.55 -.732.472.61 D 24 5.2.74 5.18.9 4.97.9 -.22.6-1.785.87 A 23 13.4 3.3 13.3 3.4 13.7 3.1.4 3.2.645.525 Cl B 25 13.1 3.7 13.2 3.7 14.6 3.9 1.4 3.7 1.846.77 4.667 meq/l C 22 12.9 3.4 12.5 3.3 15.7 3.2 3.1 3. 4.883 <.1.4 D 24 11.1 4.2 11.7 3.8 16. 5.3 4.3 3.8 5.46 <.1 A 23 2.58.45 2.55.39 2.6.39.5.18 1.253.223 Mg B 25 2.45.45 2.38.39 2.46.47.8.19 2.254.34.255 mg/dl C 22 2.62.58 2.56.49 2.66.56.1.17 2.878.9.858 D 24 2.54.53 2.52.47 2.6.65.8.35 1.41.39 A 23 7.318.37 7.32.43.23.38.281.781 ph B 25 7.324.34 7.325.46.14.49.142.888.177 C 22 7.325.3 7.317.42 -.77.45 -.83.431.911 D 24 7.33.33 7.325.52 -.51.43 -.582.566 HCO meq/l po torr pco torr A 23 17.8 2.8 18.36 2.12.72 1.61 2.9.49 B 25 18.55 2.69 18.32 2.63 -.23 2.34 -.488.63 1.2 C 22 17.82 2.53 17.46 2.5 -.36 2.97 -.568.576.388 D 24 18.37 2.1 17.79 3.52 -.58 2.52-1.133.269 A 23 15.34 17.98 13.46 15.75-2.52 14.51 -.816.424 B 25 98.38 12.41 15.14 16.26 6.76 18.56 1.822.81 1.46 C 22 15.7 14.6 12.31 16.32-2.77 1. -1.298.28.246 D 24 13.81 14.3 15.82 18.54 2.1 13.22.744.464 A 23 35.36 3.35 36.41 4.41 1.33 3.45 1.82.86 B 25 36.29 4.38 35.64 3.35 -.64 3.24 -.994.33 2.2 C 22 34.78 4.19 34.81 3.22.3 4.2.32.975.94 D 24 35.47 4.5 34.3 3.9-1.17 3.58-1.61.123 Mean S.D. -47

32 n 1st washout t t p f,p PT PT % APTT APTT % A/G Fe µg/dl UIBC µg/dl Cu µg/dl Zn µg/dl µmol/l ng/ml A 8 11.15.53 1.85.55 -.3.78-1.95.31 B 8 1.86.98 1.95 1.24.9 1.48.168.872.739 C 8 11.15.68 1.69.28 -.46.53-2.486.42.538 D 8 1.73.89 1.4.52 -.33.79-1.171.28 A 14 98.2 9.2 11.48 16.64 4.9 15.34 1.195.253 B 17 97.54 11.75 11.41 15.8 3.88 14.77 1.82.295.298 C 13 1.66 6.98 16.79 14.43 6.65 12.4 1.935.77.827 D 16 98.37 13.61 16.44 2.49 8.8 15.91 2.3.6 A 18 39.3 13.43 33.88 2.94-5.39 13.49-1.697.18 B 2 35.45 6.18 41.33 37.47 5.88 38.93.675.58.653 C 17 36.22 8.6 33.69 4.21-2.4 7.93-1.249.23.583 D 19 36.98 1.32 34.3 5.29-2.95 11.69-1.11.285 A 4 84.83 3.16 87.3 6.32 2.48 3.76 1.317.279 B 5 74.36 11.13 85.58 4.99 11.22 14.39 1.744.156.232 C 4 84.2 2.5 87.95 3.77 3.75 2.1 3.736.33.872 D 5 82.2 7.41 84.54 8.8 2.34 3.58 1.464.217 A 23 1.48.36 1.42.32 1.48.34.6.13 2.36.28 B 25 1.56.35 1.54.39 1.57.4.3.19.872.392.272 C 22 1.46.24 1.4.25 1.48.24.8.19 2.98.48.846 D 24 1.51.33 1.47.34 1.5.32.3.2.74.488 A 23 5.5 25.6 5. 19.5 -.4 21.4 -.97.923 B 25 66.6 31.8 61.5 29.6-5.1 21.6-1.176.251 1.299 C 22 55.1 16.5 64. 22.4 8.8 24.1 1.717.11.28 D 24 6. 18.3 65. 31.2 5.1 33.6.741.466 A 23 189.7 65.1 193. 57.5 3.4 34.8.467.645 B 25 169.5 53.9 186. 59.8 16.5 31.7 2.61.16.463 C 22 189.5 4.3 199.9 46.7 1.4 24.2 2.6.58.79 D 24 184.8 45.4 191.7 55.5 6.9 38.9.871.393 A 23 89.5 19.5 85. 15.4-4.5 14.6-1.467.157 B 25 96.5 24.6 88.8 19.1-7.7 12.5-3.76.5 2.27 C 22 94.3 2. 8.5 16.3-13.9 13.4-4.868 <.1.93 D 24 87.6 19.8 78.9 15.8-8.7 18.1-2.356.27 A 23 63.1 9.7 64. 8.6.9 6.7.65.522 B 25 66.9 11. 67.6 1.5.8 1.2.373.713.41 C 22 65.6 8.3 66.3 11.8.7 11.7.291.774.753 D 24 63.6 6.9 63. 11.1 -.6 1.7 -.268.791 A 23 7.17 1.7 5.32 5.39-1.84 9.31 -.95.352 B 25 5.88 4.41 6.79 13.62.91 11.1.49.686.596 C 22 4.22 2.1 4.25 3.19.2 2.8.38.97.619 D 24 4.45 1.87 3.55 1.31 -.9 1.84-2.42.25 A 23 7.34 3.84 7.18 2.57 -.16 2.2 -.342.736 B 25 7.28 1.77 25.2 97.68 17.92 97.7.923.365.861 C 22 23.89 73.59 21.21 66.77-2.68 7.9-1.775.9.464 D 24 7.57 2.22 5.97 1.98-1.6 1.93-4.79 <.1 Mean S.D. -48

32 n 1st washout t t p f,p A 23 1336.4 36.2 1394.7 45.8 58.3 263.2 1.62.3 A B 25 1192.3 375.9 1291.8 44.7 99.4 178.3 2.788.1.337 ng/ml C 22 1427.4 379.9 1437.7 354.2 1.3 327.6.148.884.799 D 24 1368.6 49.1 1384.6 547.7 16. 273..286.777 A 23 814.5 44.5 826. 462.8 11.5 152.1.363.72 B 12 B 25 943.1 97.3 86.6 738.9-136.5 243.1-2.87.1 2.598 pg/ml C 22 19.8 844.7 927. 699.3-82.8 217.5-1.786.89.57 D 24 69.3 478.8 73. 387.6 12.7 214.2.291.774 A 23 13.54 7.99 12.2 6.78-1.34.99 -.921.367 1,25(OH) 2 D B 25 13.41 8.45 13.89 8.21.48 4.34.553.586.548 pg/ml C 22 16.12 6.5 14.83 6.66-1.3 6.65 -.914.371.651 D 24 13.14 5.92 12.23 5.66 -.91 5.84 -.766.452 A 23.297.179.278.153 -.19.173 -.519.69 24,25(OH) 2 D ng/ml 25(OH)D ng/ml E mg/dl PK ng/ml MK-4 ng/ml MK-7 ng/ml mg/dl B 25.314.188.292.176 -.21.154 -.686.499.817 C 22.283.182.233.139 -.5.171-1.387.18.448 D 24.242.128.219.14 -.23.97-1.155.26 A 23 23.53 1.28 21.58 9.63-1.94 5.49-1.699.13 B 25 24.83 8.57 24.13 9.2 -.7 4.9 -.714.482.618 C 22 27. 9.13 23.98 7.78-3.1 6.61-2.14.44.65 D 24 25.53 1.5 23.35 8.9-2.18 5.16-2.74.5 A 23 1.39.393 1.327.358.18.168.59.616 B 25 1.31.428 1.269.43 -.32.16 -.999.328 1.954 C 22 1.355.319 1.352.323 -.3.222 -.67.947.127 D 24 1.27.31 1.179.297 -.91.193-2.318.3 A 23 1.15.73 1.236.999.131 1.238.57.617 B 25.812.43.795.822 -.16.888 -.92.927 1.148 C 22 1.115 1.17 1.268 1.342.153 1.256.571.574.334 D 24.914.535.787.577 -.13.551-1.129.271 A 23 13.343 63.361 5.319 24.564-8.24 38.798 -.992.332 B 25.674 2.674 1.16 4.415.342 1.748.977.338.822 C 22.167.16.17.141.3.113.114.911.485 D 24.233.25.183.177 -.55.264-1.5.326 A 23 2.586 3.341 2.492 3.644 -.94 4.27 -.112.912 B 25 2.532 3.961 2.2 3.546 -.53 5.571 -.476.639.21 C 22 2.293 3.2 2.4 2.721.17 3.942.128.9.896 D 24 2.118 3.372 1.876 2.311 -.3 3.427 -.42.678 A 23 326.8 94.9 31.8 75.7-15.9 51.5-1.444.163 B 25 321. 9.3 314.7 98.5-6.3 64.5 -.489.629.832 C 21 34.3 82.1 337.2 65.2-6.6 71.2 -.411.686.48 D 24 32.5 71.4 327.1 149.9 24.5 119.2 1.8.324 Mean S.D. -49

4 33 A 23 19 82.6%B 25 18 72.%C 22 13 59.1% D 24 12 5.% 12 A NOS NEC 1 2 B 1 2 C NOS NOS 1 3 D NOS NOS C- 1 5 A B C D 33 95%CI 11 8 2 2 47.8 34.8 8.7 8.7 26.8-69.4 23 47.8 82.6 91.3 1 9 9 5 2 36. 36. 2. 8. 18.-57.5 25 36. 72. 92. 1 7 6 6 3 31.8 27.3 27.3 13.6 13.9-54.9 22 31.8 59.1 86.4 1 5 7 7 5 2.8 29.2 29.2 2.8 7.1-42.2 24 2.8 5. 79.2 1 % % P P P 8.mg/dL P P A B 2 C D 1 1.5g/A 3.g/B C D P 8.mg/dL P C D 2 P A B C 3 D 2 1.5g/A 3.g/B 6.g/ C D -5

62 66.% 127 NOS D 8 4 D 3 P P 8.mg/dL 3.g/ P 8.mg/dL 6.g/ P 4. 6.mg/dL -51