L-NAME 10 mg/kg Control. N=5~6 * p<0.05. AG 10 mg/kg AG 5 mg/kg. * AG 20 mg/kg. Normal days

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3 & # -L= K=JE B+ E?,= =CA 6DA= E = IMAHA E A@%@=OI=BJAHJDA IAJ B,55 JHA=J A J E A=JAJDA K? =CA B-L= I> KAM=IE A?JA@E JH=LA KI O! E >AB HAI=?HEBE?A 6DA? M=I B H = E I KJE B H E KJAI )BJAHEJIE AHIE E B H = E JDA =HCA> MA M=I FA A@= CJDA AIA JAHE?=JJ=?D A E A@ =?H I? C E?H I? FAN B HA@A = DOFAHA E= AH IE 6DA=HA= B =?H I? FE?= OLEIE> A AIE IM=I A=IKHA@KIE C 10E =CA $ 10 *AJDAI@=, 75) 6DA A CJD BJDA? M=I= E A@ 1 E A@ =?H I? FE?= O =?? H@E CJ JDAB ME C?HEJAHE=BEHIJHAF HJA@>O+ HA H = IJ OI BJIJ LAHOI BJIJ! BA?AII? HA H =? HIJ >H M? HIJ HA@@EID? HIJ! 0EIJ CE?= -L= K=JE 6DA@EIJ=? M=IAN= E A@MEJD= ECDJ E?H I? FA 6DAJEIIKAI= F AIMAHAE AHIA@E B H = E IA?JE A@=J# A@MEJDDA =J NO E IE 6DAIALAHEJO BJEIIKA IA?JE IM=ICH=@A@ E?H I? FE?= O=IID ME C= H = =FFA=H=?A BE JH=JAI BI = H I O HFD K? A=H AK??OJAIE JDA = E =FH FHE= K? I=AMEJDID= M H@AAF AH IE K?AH=JE,AJAH E =JE BE 5 4 )ANFHAIIE >OHALAHIAJH=?HEFJE F O AH=IA?D=E HA=?JE J= 4 )BH H=J? E? K? I=M=IANJH=?JA@KIE C5AF=I 4 )1 =?= =E6AIGKA O J =F= 6 J= 4 )FHE A@>O M=IHALAHIA JH= ) IO JDAIEI EJ4ALAH 6H=)?A= FD=6 O > =F= =BJAHJHA=J A JMEJD, =IA16 O > =F= J HA LA? J= E =JE BH CA E?, ) 6DA2+4FHE AHIB HH=JE 5MAHAIA IA # JEIA IA# /)6/66/6)/+/+6/6/6/6+ )!$#>FMDE AJD IAB HH=JA 5MAHAIA IA# = JEIA IA# 6)6/++)/+)+)/+6)+)/6/)!%%>F ) = EGK J BJDA46HA=?JE F =JAE!?O? AIMEJD # E B@A =JKH=JE =J'# E B ANJA IE =J$& +KIE CJDA)@L= J=CA F O AH=IA ENJKHA =JDAH =?O? AH 6) -4)62 " )F HJE BJDA2+4 ENJKHAM=IA A?JH FD HAIA@E &=C=H IACA E 6-)>KBBAH" 6HEI -,6) =?AJE?=?E@ F0 & M=IIJ=E A@ MEJDAJDE@EK >H J CH=FDA@ A@E J F/- 6A=IO LA?J H2H AC= E A@>OJDA@E@A NO?D=E JAH E =JE =*EC,OAJAH E =J HL! +O? A5AGKA?E C EJ*E IOIJA I KIE C= =KJ =JE?, )IAGKA?AH )*12HEI!/A AJE?) = OIAH *E IOIJA I 6DAIAGKA?A = O A@ KIE CJDA* )56FH CH= *+1 2HAF=H=JE B,HKCI 6DA@HKCIKIA@MAHA@ANJH= IK 9= I= = =F= = E CK= E@E A / EJH =HCE E A AJDO AIJAH ) -5EC = 5J KEI I> KA AH?,=H IJ=@J /AH = O ) E CK= E@E ) -MAHA@EII LA@E 'I= E AI KJE -L= I> KAM=I@EII A@M=JAH A@E=JA O>AB =@ E EIJAHA@ H= OE =L K A B # HE JH=LA KI OE =L K A B

4 & $ 5J=JEIJE?I,=J==HAFHAIA JA@=IJDA A= 5- B#J $H=JIFAHCH KF 5J=JEIJE?= = = OIEIM=IFAHB H A@ KIE CJDAJM J=E A@,K AJJI K JEF A? F=HEI JAIJ KAI BF #MAHA? IE@AHA@ IEC EBE?= J BBA?J B) E CK= E@E ) -,55 EJEI K? I= AIE I 6DA= E = IJHA=JA@MEJD!,55B H%@=OI@ALA FA@ IO FJ I B=?KJA? EJEI=J= E?E@A?A B,E=HHDA=M=IBEHIJ@AJA?JA@ JDA! JDA" BJHA=J A J + EJEIM=I=?? F= EA@>O IALAHA II AIE I? HAM=I! # $ & E JDEICH KF 6HA=J A JMEJD= E CK= E@E AB H$@=OI= A E H=JA@JDA,55 EJEIE J = AH MEJDIKFFHAIIE > AA@E C =IMA =IJDA II 6DA K? =CAI? HA E JDACH KFIJHA=JA@MEJD# C C B= E CK= E@E AM=I %& & '! ## && %!!# % HAIFA?JELA O JDAABBA?J=J C C>AE C IEC EBE?= J OMA= AH=I? F=HA@J JDA? JH E AMEIA JDEI=CA JCELA =J C CE JDA =IJ!@=OI B,55JHA=J A J = I ID MA@=IEC EBE?= JHA@K?JE E JDAIALAHEJO B AIE I? F=HA@J JDA? JH JDA@= =CAI? HA>AE C&$ " &.EC 6DEIJHA=J A JE JDABE =!@=OI= I IEC EBE?= J OFHALA JA@JDA II 6=> A * AA@E CE 4=JI=BJAH%,=OI,55 6HA=J A J /H KF 1?E@A?A 1?E@A?A B BH=JI C=E B,E=HHDA= 4A?J= > AA@E C H = # # "!$ # # + JH $ " '# " &' = $ $ # $ )/# C CB H$@=OI $ ' #$!!" = $ $ " $ )/ C CB H$@=OI $ % #! " $ = # $! $ )/ C CB H$@=OI $! && # $ = >! $ $ )/ C CB HBEHIJ!@=OI $ ##! # = $ $ # $ )/ C CB H =IJ!@=OI $ " #! = >! $! $ ) - C CB H$@=OI $ " " # = # $ # $ ) - C CB HBEHIJ!@=OI $ "!! # = $ $ $ $ ) - C CB H =IJ!@=OI $ #! # = $ $ # $ -NFAHE A J=? H=JIMEJD=!,55 I KJE E CM=JAHB H%@=OI ) E CK= E@E A)/ # C H ) - C CM=I=@ E EIJAHA@F JME?A@=E OB JDABEHIJ!@=OI HJDA =IJ!@=OI B,55 JHA=J A J,=J= CAI=HA FHAIA JA@=IJDA A= 5- B# $H=JI 1?E@A?A B@E=HHDA= HHA?J= > AA@E C A= IJDA K >AH B= E = IID ME C BJDA@E=HHDA=I? HA HA 5EC EBE?= J@EBBAHA?A=J F # =BH H = >BH? JH

5 & % 6 Disease activity index N=5~6 * p<0.05 L-NAME 10 mg/kg Control AG 10 mg/kg AG 5 mg/kg * AG 20 mg/kg days Normal.ECKHA -BBA?JI B= E CK= E@E ) - EJEI -NFAHE A J=? H=JIMEJD=!,55 I KJE E CM=JAHB H%@=OI ) E CK= E@E A# C C H ) - C CM=I=@ E EIJAHA@ F JME?A@=E HA! HA!,=J==HAFHAIA JA@=IJDA A= 5-B H# $H=JI 5EC EBE?= J@EBBAHA?ABH? JH =JF # MEJDIKFFHAIIE > AA@E C6=> JDA ) -CELA =J C CB H$@=OI HB HJDA =IJ!@=OI@KHE C,55JHA=J A J@E@ J=BBA?JJDAANFAHE A J=? EJEI HA LAH JDEI=CA JCELA E JDABEHIJ!@=OI B,55JHA=J A J?=KIA@=I ECDJ JD KCD JIEC EBE?= J =CCH=L=JE B? EJEI JDA@= =CAI? HA>AE C!#& # $ 6=> + A CJD )BJAH%@=OIJHA=J A E CM=JAH JDA? M=IID HJA A@E = = E = I 6DA? A CJD B,55 JHA=JA@? JH = E = I M=I' "! " IEC EBE?= J O AIIJD= JD=J B H = H=JI % # &.EC # 6DA,55 HJA E C BJDA? M=IE FH LA@E J = AHB ME C=@ E EIJH=JE B= E CK= E@E A# C CB H $@=OI EBE?= JABBA?JM=I >IAHLA@=JJDADECDAIJ@ IA JDAL= KA>AE C # " " " 5E E =H O = E CK= E@E ACELA =J C CE JDA =IJ!@=OI B,55JHA=J A J= I HAIJ HA@JDA? I A CJDJ $! MDE?DEI IEC EBE?= J OCHA=JAHJD= JD=JE JDA? JH CH KF *O? JH=IJ ) -CELA =J C CB HAEJDAH= $@=OI JDABEHIJ!@=OI HJDA =IJ!@=OI B,55 JHA=J A JE B KA?AJDA? ID HJA E C.EC # 0EIJ CO *ODEIJ CE?= AN= E =JE F=JD CE?=?D= CAM=I@AJA?JA@ E JDA? E? K? I= B H = = E = I 0 MALAH JDA,55 JHA=JA@? JH H=J K? I=ID MA@A@A IE I K?AH=JE BE JH=JAI B F O HFD K? A=H AK??OJAI=IMA =I O FD?OJAI 6DA E?H I? FE?= CH=@E C E JDAIALAHEJO BJEIIKA@= =CAM=IHA =H => OHA@K?A@>O= E CK= E@E A>KJ J>O ) - MDA JDAOMAHACELA B H$@=OI@KHE C,55JHA=J A J 1 JDA

6 & &.ECKHA -BBA?J B= E CK= E@E A)/? E?K?AH=JE =HA=E,55 EJEI -NFAHE A J=? H=JIMEJD=!,55 I KJE E CM=JAH B H%@=OI )/# C CM=I=@ E EIJAHA@F JME?A@=E OB H= $@=OI HJDABEHIJ!@=OI H =IJ!@=OI B,55 JHA=J A J,=J==HAFHAIA JA@=IJDA A= 5-B H# $H=JI 5EC EBE?= JH =JF #.ECKHA! -BBA?J B ) -? E?K?AH=JE =HA=E,55 EJEI -NFAHE A J=? H=JIMEJD=!,55 I KJE E CM=JAHB H%@=OI ) - C CM=I=@ E EIJAHA@F JME?A@=E OB H= $@=OI HJDABEHIJ!@=OI H B,55 JHA=J A J,=J==HAFHAIA JA@=IJDA A= 5-B H# $H=JI

7 & '.ECKHA" -BBA?J B= E CK= E@E A)/? A CJDE,55 EJEI -NFAHE A J=? H=JI>O!MEJD=!,55 I KJE E CM=JAHB H %@=OI )/# C CM=I=@ E EIJAHA@F JME?A@=E OB H= $@=OI HJDABEHIJ!@=OI H =IJ!@=OI B,55 JHA=J A J,=J==HAFHAIA JA@=IJDA A= 5-B H# $H=JI 5EC EBE?= J@EBBAHA?A=J F # BH H = BH? JH.ECKHA# -BBA?J B ) -? A CJDE,55 EJEI -NFAHE A J=? EJEI H=JIMEJD=!,55 I KJE E CM=JAHB H%@=OI ) - C CM=I=@ E EIJAHA@F JME?A@=E OB H= $@=OI HJDABEHIJ!@=OI H =IJ!@=OI@KHE C,55 JHA=J A J,=J==HAFHAIA JA@=IJDA A= 5-B H# $H=JI 5EC EBE?= J@EBBAHA?ABH H = H=JI =JF #

8 &! Normal 3% DSS 3% DSS + AG (20 mg/kg) 3% DSS+L-NAME (10 mg/kg).eckha$ /H II=FFA=H=?AI B? E? AIE H=JI + H=JI MEJD=!,55 I KJE E CM=JAHB H%@=OI ) E CK= E@E A)/ C C H ) - C CM=I=@ E EIJAHA@F JME?A@=E OB H$@=OI JAJD=J,55JHA=J A J?=KIA@= =H A@@A?HA=IAE JDA? A CJD HJA E CM=IE FH LA@>OJHA=J A JMEJD)/ >KJ J ) - A B Normal Control (3% DSS) C D DSS+AG (20 mg/kg) DSS+L-NAME (10 mg/kg).eckha% 0EIJ CO BH=J? E? K? I= ) H = H=J *!,55 JHA=JA@? JH +!,55 C C B= E CK= E@E A)/,!,55 C C B ) - -NFAHE A J=? EJEI H=JIMEJD=!,55 I KJE E CM=JAHB H%@=OI )/ C C H ) - C CM=I=@ E EIJAHA@F JME?A@=E OB H$@=OI

9 &! C C B= E CK= E@E A JDA? E? K? I=ID MA@ O I ECDJF=JD CE??D= CAI MDE?D =H A@ O? JH=IJA@J JDA? JH H=J K? I=.EC % 6DADEIJ CE?= CIF=H= A A@JDA =?H I? FE?= OLEIE> A@= =CA -NFHAIIE BE 5 4 )E 4=J+ 9DE AJDAANFHAIIE BA 5 4 )M=I >IAHLA@E JDA H = H=J? JDACA AANFHAIIE BE 5M=I J@AJA?JA@E JDA K? I= 0 MALAH JDA ANFHAIIE BE 5 4 )M=IB JDA? E? K? I=BH JDA" B,55JHA=J A A CJDAJHA=J A J.EC & 6DAA 5 4 )FH LA@J >AANFHAIIA@IJA=@E OE,55 JHA=JA@H=JI, JEI M JD=J,55 A J=? EJEID=IIE E =HDEIJ CE?= F=JD CE?=?D=H=?JAHEIJE?IJ DK = K?AH=JELA? EJEI" 6DAFHAIA JIJK@O G3PDH enos inos Normal days DSS treatment.eckha& = = OIEIB HE 5 4 )E H=J? E? K? I=@KHE C,55 JHA=J A J 6DAANFHAIIE BE 5 4 )M=I@AJAH E A@E H = H=J " =BJAHJDA IAJ B,55JHA=J A J

10 A?JELAE 5E DE>EJ H= E CK= E@E A=BB H@A@= FH JA?JELAABBA?J =,55 EJEIE H=JIMDA CELA B H= $@=OI HB H JDA =IJ!@=OI B,55JHA=J A J >KJM=IE ABBA?JELAMDA CELA OB HJDABEHIJ!@=OI 9A= I B IA A?JELA 5E DE>EJ H ) -=@ E EIJAHA@ B H= $@=OI H =IJ!@=OI B,55JHA=J A J@E@ J=BBA?J? E?E B = =JE E HA ) -CELA E JDABEHIJ!@=OI B,55 JHA=J A =CCH=L=JAJDA? E?E B = =JE AIE I 6DAIAHAIK JI? A=H H AB CA KI E JDA@ALA F A J BK?AH=JELA? H=JI>O,55 =FH JA?JELAABBA?J>O? 5 A J= ABBA?J>OE 5 7?AH=JELA? EJEIEI= E B = =J HO@EIA=IA? BE A@J JDA K? J = AIIAHANJA J JDA=@ =?A JIK> K? I= ) JD F A J= FH?AII BJDEI@EIA=IAHA =E K M JDA?D=H=?JAHEIJE?I BJDA@EIA=IA=HA ID=HA@>O JDAHE B = =J HO@EI H@AHI BJDACKJ EA =?JEL=JA@ AKJH FDE =?H FD=CAI=HAJDA = H? F A JI BJDA=?JELA AIE IE K?AH=JELA? EJEI # $ =HCA K >AHI B AKJH FDE =?H FD=CAIA JAHJDAE KHA@ K? C=?KJAE B = =JE A=@E CJ = B NOCA H=@E?= % * JDE 5ANFHAIIE =HAHAF HJA@ OE?HA=IA@E JDAAFEJDA E=?A =?H FD=CAI BJDAE B = A@ K? I=E F=JEA JI MEJDE B = =J HO> ' 6DAE JAH=?JE B NOCA H=@E?= HAIK JIE JDAB H =JE B?OJ J NE? EJH CA IFA?EAI FAH NO EJHEJA MDE?DEI M J JAE EJH=JE =IMA =I EFE@FAH NE@=JE JDA IALAHEJO B,55 EJEIM=IIEC EBE?= J O=JJA K=JA@E E?ACA AJE?= JE E 5 5E E =HHAIK JIMAHA >J=E A@>O HEAC IJAE AJ= MD HAF HJA@JD=J KHE AE JAIJE = E B = =JE M=IFHALA JA@>OJHA=J A J MEJD=DECD OIA A?JELAE 5E DE>EJ H"9 0 MALAH D=I= E F HJ= JH A= I E JDA H = FDOIE CO BJDA? ' 1 B=?J JDAABBA?JI B 5E DE>EJ HI? EJEI=HA? JH LAHIE=! # 5 A=KJD HI? IE@AH =I= E B = =J HO =H AH HJA@JDA E F HJ=?A BJDEIBHAAH=@E?= E JDAF=JD CA AIEI BANFAHE A J=? EJEI 9A >IAHLA@E JDAFHAIA JIJK@OJD=JJDAIA A?JELAE 5E DE>EJ H = E CK= E@E AIEC EBE?= J OHA@K?A@JDAIALAHEJO B? E? AIE IMDA =@ E EIJAHA@B H= $@=OI HB HJDA =IJ!@=OI B,55 JHA=J A J 6DEI=CA J= I FHALA JA@JDA? BH ID HJA E A E H=JA@JDADEIJ CE?= E B = =JE E JDEI? *O? JH=IJ JDA IA A?JELA 5E DE>EJ H ) =CCH=L=JAJDA? E? AIE IMDA CELA B HJDABEHIJ!@=OI B,55JHA=J A J = JD KCDEJD=@ ABBA?JMDA CELA B H= $@=OI HJDA 6DAIAHAIK JIJ CAJDAHMEJDJDA KJ? A B= E CK= E@ AJHA=J A J IKCCAIJ=F=H=@ NE?= H AB E 5E F A J BANFAHE A J=? EJEI CA KI D=I=@K= E B KA?A,55 EJEI C JDA 5EI O A JDA 5 E JDABE =!@=OI B,55JHA=J A JEI E A O@AJHE A J= MDE AJD=J@AHELA@BH? 5EI? IE@AHA@J >A>A ABE?E= E B? EJEI MA >IAHLA@

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