KORELASI ANTARA KADAR MATRIKS 9, LAJU ENDAP DARAH, FAKTOR REUMATOID, DAN LAMA SAKIT DENGAN GAMBARAN RADIOLOGIS PADA PASIEN ARTRITIS REUMATOID | Aji | Jurnal Penyakit Dalam Indonesia 1 SM

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Korelasi Antara Kadar Matriks

Metalloproteinase 9, Laju Endap Darah, Faktor

Reumatoid, dan Lama Sakit dengan Gambaran

Radiologis pada Pasien Artritis Reumatoid

Giri Aji1_{, Sumariyono}2_{, Kahar Kusumawidjaja}3_{, Murdani Abdullah}4

1_{De p a rte m e n Ilm u Pe nya kit Da la m FKUI}

2_{Divisi Re um a to lo g i, De p a rte m e n Ilm u Pe nya kit Da la m FKUI/ RSC M}

3_{De p a rte m e n Ra d io lo g i, De p a rte m e n Ilm u Pe nya kit Da la m FKUI/ RSC M} 4_{Divisi G a stro e nte ro lo g i, De p a rte m e n Ilm u Pe nya kit Da la m FKUI/ RSC M}

ABSTRAK

Pe nd a hulua n. Artritis Re um a to id (AR) m e rup a ka n p e nya kit a uto im un d e ng a n e tio lo g iya ng b e lum je la s, g e ja la uta m a d a ri AR a d a la h ke ra d a ng a n p a d a se nd i ya ng d ita nd a i d e ng a n sino vitis sim e tris d a n e ro si tula ng , w a la up un p e rja la na n p e nya kit AR sulit d id ug a d e ng a n sifa t kro nik-re m isi-e ksa se rb a si na m un se c a ra um um ha sil a khir d a ri AR a d a la h d e fo rm ita s se nd i. Pe ne litia n te ra khir p a d a AR m e nunjukka n a d a nya o ve re ksp re si d a ri se jum la h e nzim ma trix me ta llo p e o te ina se s (MMPs)

ya ng m e m p unya i ke m a m p ua n d e g ra d a si ko m p o ne n ko la g e n d a m m a triks e kstra se lule r tula ng ra w a n Be b e ra p a p e ne litia n m e ne m uka n ke te rlib a ta n MMP-2,MMP-9, MMP-1 ,MMP-8 d a n MMP-3 p a d a p e nya kit AR. Pe ne litia n d i Ta iw a n o le h C ha ng

<KPHQXQMXNNDQSHQLQJNDWDQNDGDUGDQDNWLÀWDV003SDGDSDVLHQ$5GL7DLZDQGLEDQGLQJNDQSDGDSRSXODVLQRUPDO

G ia nne lli m e la p o rka n p e ning ka ta n ka d a r MMP-2, MMP- 9, Tissue Inhib ito r Ma trix p ro te ina se 1 d a n Tissue Inhib ito r Ma trix p ro te ina se 2 p a d a p a sie n d e ng a n AR d a n a rtritis p so ria sis, G rub e r jug a m e la p o rka n a d a nya p e ning ka ta n ya ng b e rm a kna d a ri ka d a r MMP-9 a ta u g e la tina se B p a d a se rum p a sie n AR. Pe ne litia n ini b e rtujua n untuk m e ning ka tka n p e m a ha m a n

PHQJHQDLSHUDQ003SDGDSDWRÀVLRORJLNHUXVDNDQVHQGL$5VHUWDPHQFDULNRUHODVLDQWDUDNDGDU003ODMXHQGDS

d a ra h (LED), fa kto r re um a to id d a n la m a sa kit d e ng a n g a m b a ra n ra d io lo g is p a d a p a sie n AR.

Me to d e . Pe ne litia n ini m e ng g una ka n stud i p o to ng linta ng a na litik d e ng a n m e to d e sa m p ling ko nse kutif ya ng d ila kuka n d i p o liklinik Re um a to lo g i/ Ilm u Pe nya kit Da la m RSUPN C ip to Ma ng unkusum o . Se b a g a i va ria b e l b e b a s a d a la h : ka d a r m a triks m e ta llo p ro te ina se 9, la ju e nd a p d a ra h (LED) , fa kto r re um a to id d a n la m a sa kit se m e nta ra va ria b e l te rg a ntung a d a la h sko r ra d io lo g is Sha rp .

Ha sil. Da ri 46 sub je k p e ne litia n d id a p a tka n p e ning ka ta n ka d a r re ra ta MMP-9 ya ituse b e sa r 104,82 ng / m l, re ra ta LED 58,5 m m / ja m , re ra ta ka d a r fa kto r re um a to id 57,13 IU/ m l d a n re ra ta la m a sa kit a d a la h 4,83 ta hun. Ko re la si a nta ra ka d a r MMP-9 d e ng a n sko r e ro si tula ng se c a ra ra d io lo g is a d a la h r=0,3 d e ng a n p =0,02 (b e rm a kna ), se m e nta ra ko re la si a nta ra la m a sa kit d e ng a n g a m b a ra n ra d io lo g is ( sko r Sha rp ) r=0,36 d e ng a n p =0,014 (b e rm a kna ). Ko re la si a nta ra LED, d a n fa kto r re um a to id d e ng a n g a m b a ra n ra d io lo g is a d a la h r=0,10,p =0,24;d a n r=0,19,p =0,09.

Sim p ula n. Did a p a tka n p e ning ka ta n ka d a r MMP-9 p a d a p a sie n AR, ka d a r MMP-9b e rko re la si d e ng a n g a m b a ra n e ro si tula ng se c a ra ra d io lo g is, la m a sa kit b e rko re la si d e ng a n g a m b a ra n ra d io lo g is (sko r Sha rp ), Fa kto r re um a to id d a n LED tid a k b e rko re la si d e ng a n g a m b a ra n ra d io lo g is (sko r Sha rp ).

Ka ta kunc i : a rtritis re um a to id , m a triks m e tra llo p ro te ina se -9

PENDAHULUAN

ƌƚƌŝƟƐZĞƵŵĂƚŽŝĚ;ZͿĂĚĂůĂŚƉĞŶǇĂŬŝƚŬĞƌĂĚĂŶŐĂŶ ƐĞŶĚŝǇĂŶŐďĞƌƐŝĨĂƚŬƌŽŶŝŬĚĞŶŐĂŶŚĂƐŝů ĂŬŚŝƌĚĞĨŽƌŵŝƚĂƐ ƐĞŶĚŝĂŬŝďĂƚĚĂƌŝŬĞƌƵƐĂŬĂŶƚƵůĂŶŐƌĂǁĂŶĚĂŶŬĞƌƵƐĂŬĂŶ ƚƵůĂŶŐ͘ WĞƌũĂůĂŶĂŶ Z ƐĞŶĚŝƌŝ ƐĞƌŝŶŐ ƐƵůŝƚ ĚŝĚƵŐĂ ĚĞŶŐĂŶ ƐŝĨĂƚŶǇĂǇĂŶŐŬƌŽŶŝŬͲƌĞŵŝƐŝͲĞŬƐĂƐĞƌďĂƐŝ͘

ƌƚƌŝƟƐ ZĞƵŵĂƚŽŝĚ ;ZͿ ĚŝŬĂƌĂŬƚĞƌŝƐƟŬĂŶ ĚĞŶŐĂŶ

ƐŝŶŽǀŝƟƐ ƉƌŽůŝĨĞƌĂƟĨ ŬƌŽŶŝŬ͕ ŚŝƉĞƌƉůĂƐŝĂ ƐĞů ͕ ŝŶĮůƚƌĂƐŝ ƐĞů ƉĞƌĂĚĂŶŐĂŶ͕angiogenesis pada sublining cell layer͕

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zinc-ĚĞƉĞŶĚĞŶƚĞŶĚŽƉĞƉƟĚĂƐĞǇĂŶŐŵĞŵƉƵŶǇĂŝŬĞŵĂŵƉƵĂŶ metalloproteinases͘ ĞďĞƌĂƉĂ ƉĞŶĞůŝƟĂŶ ŵĞŶĞŵƵŬĂŶ

ŬĞƚĞƌůŝďĂƚĂŶDDWͲϮ͕DDWͲϵ͕DDWͲϭ͕DDWͲϴĚĂŶDDWͲϯ ĚŝŶŝůĂŝƐĞĐĂƌĂƌĂĚŝŽůŽŐŝƐĚĞŶŐĂŶhaplotypeŐĞŶDDWϯ͘ϯ͕ϰ

Matrix metalloproteinase ϵ;DDWͲϵͿĚŝĞŬƐƉƌĞƐŝŬĂŶ

ƉĂĚĂ ŽƐƚĞŽŬůĂƐ͕ ĚĂŶ ƉĂĚĂsel giant cell tumor. WĂĚĂ Z͕ ŬĂĚĂƌDDWͲϮ͕DDWͲϵ͕Tissue Inhibitor Matrix proteinase

1 dan Tissue Inhibitor Matrixproteinase 2 pada pasien ĚĞŶŐĂŶZĚĂŶĂƌƚƌŝƟƐƉƐŽƌŝĂƐŝƐĚĂŶ'ƌƵďĞƌŵĞůĂƉŽƌŬĂŶ

American College of Rheumatology ;ZͿ ϭϵϴϳ ǇĂŶŐ

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dĂďĞůϳ͘<ŽƌĞůĂƐŝĂŶƚĂƌĂŬĂĚĂƌ>ĚĞŶŐĂŶƐŬŽƌĞƌŽƐŝƚƵůĂŶŐ

Variabel ^ŬŽƌĞƌŽƐŝƚƵůĂŶŐ

<ŽĞĮƐŝĞŶ<ŽƌĞůĂƐŝ p

> 0.11 0.21

,ĂƐŝů Ƶũŝ ŬŽƌĞůĂƐŝ ďŝǀĂƌŝĂƚ ĂŶƚĂƌĂ ůĂŵĂ ƐĂŬŝƚ ĚĞŶŐĂŶ ƐŬŽƌ^ŚĂƌƉŵĞŶĚĂƉĂƚŬĂŶŚĂƐŝůƉϬ͕Ϭϭϰ;ďĞƌŵĂŬŶĂͿĚĞŶŐĂŶ ŬŽŽĨĞƐŝĞŶŬŽƌĞůĂƐŝƌϬ͕ϯϲϭ;ŬŽƌĞůĂƐŝƐĞĚĂŶŐͿ;dĂďĞůϴͿ͘

Tabel 8. Korelasi antara lama sakit dengan kerusakan sendi

Variabel <ĞƌƵƐĂŬĂŶƐĞŶĚŝ;^ŬŽƌ^ŚĂƌƉͿ

<ŽĞĮƐŝĞŶ<ŽƌĞůĂƐŝ p

>ĂŵĂƐĂŬŝƚ;dĂŚƵŶͿ 0.361 0.014

hũŝ<ŽƌĞůĂƐŝ^ƉĞƌŵĂŶ;^ĞďĂƌĂŶĚĂƚĂƟĚĂŬŶŽƌŵĂůͿ

WĂĚĂ ƉĞŶĞůŝƟĂŶ ŝŶŝ ƐĞŵƵĂ ƐƵďũĞŬ ƉĞŶĞůŝƟĂŶ ŵĞŶĚĂƉĂƚŬĂŶ ƚĞƌĂƉŝ DZ^ ;ŝƐĞĂƐĞ DŽĚŝĨǇŝŶŐ ŶƟ

Rheumatoid DrugsͿ ƐĞďĂŐĂŝ ǀĂƌŝĂďĞů ƉĞƌĂŶĐƵ͕ ĚĂŶ

ǁĂůĂƵƉƵŶ ďĞďĞƌĂƉĂ ƉĂƐŝĞŶ ŵĞŶĚĂƉĂƚ ƚĞƌĂƉŝ ŬŽŵďŝŶĂƐŝ DZ^ ŶĂŵƵŶ ƐĞŵƵĂ ƉĂƐŝĞŶ ŵĞŶĚĂƉĂƚ ƚĞƌĂƉŝ ŵĞƚŚŽƚƌĞǆĂƚ ƐĞďĂŐĂŝ ƐĂůĂŚ ƐĂƚƵ ƵŶƐƵƌ ĚĂůĂŵ DZ^ ƐĞŚŝŶŐŐĂ ĚĂůĂŵ ĂŶĂůŝƐŝƐ ŵƵůƟǀĂƌŝĂƚ DZ^ ƟĚĂŬ ďĞƌŵĂŬŶĂƐĞďĂŐĂŝǀĂƌŝĂďĞůƉĞƌĂŶĐƵĚĞŶŐĂŶpсϬ͕ϭϰϲ͘

,ĂƐŝůĂŶĂůŝƐŝƐŵƵůƟǀĂƌŝĂƚƌĞŐƌĞƐŝůŝŶŝĞƌĂŶƚĂƌĂǀĂƌŝĂďĞů ǇĂŶŐďĞƌŚƵďƵŶŐĂŶĚĞŶŐĂŶŐĂŵďĂƌĂŶƌĂĚŝŽůŽŐŝƐƉĂƐŝĞŶZ ǇĂŶŐŵĞŵŝůŝŬŝŬĞŵĂŬŶĂĂŶƉфϬ͕ϮϱƚĞƌůŝŚĂƚƉĂĚĂdĂďĞůϵ͘

dĂďĞů ϵ͘ ŶĂůŝƐŝƐ ŵƵůƟǀĂƌŝĂƚ ǀĂƌŝĂďĞů ǇĂŶŐ ďĞƌŚƵďƵŶŐĂŶ ĚĞŶŐĂŶŐĂŵďĂƌĂŶƌĂĚŝŽůŽŐŝƐƉĂƐŝĞŶZ

Variabel ^ŬŽƌ^ŚĂƌƉ;ƉǀĂůƵĞͿ

DDWͲϵ Ϭ͕ϲϭϮ

> Ϭ͕ϰϭϭ

>ĂŵĂƐĂŬŝƚ Ϭ͕Ϭϰϲ

&ĂŬƚŽƌZĞƵŵĂƚŽŝĚ Ϭ͕ϱϭϵ

EŝůĂŝ ŬŽƌĞůĂƐŝ ďĞƌĚĂƐĂƌŬĂŶ ĂŶĂůŝƐŝƐ ŵƵůƟǀĂƌŝĂƚ ƌĞŐƌĞƐŝůŝŶŝĞƌǀĂƌŝĂďĞůǇĂŶŐďĞƌŬŽƌĞůĂƐŝĚĞŶŐĂŶŐĂŵďĂƌĂŶ ƌĂĚŝŽůŽŐŝƐƉĂƐŝĞŶZĚŝĚĂƉĂƚŬĂŶƐĞďĞƐĂƌϬ͕Ϯϵϵ;dĂďĞůϭϬͿ͘

dĂďĞů ϭϬ͘ EŝůĂŝ ŬŽƌĞůĂƐŝ ďĞƌĚĂƐĂƌŬĂŶ ĂŶĂůŝƐŝƐ ŵƵůƟǀĂƌŝĂƚ ǀĂƌŝĂďĞů ǇĂŶŐ ďĞƌŚƵďƵŶŐĂŶ ĚĞŶŐĂŶ ŐĂŵďĂƌĂŶ ƌĂĚŝŽůŽŐŝƐ ƉĂƐŝĞŶZ

Variabel _P r

>ĂŵĂƐĂŬŝƚƚĞƌŚĂĚĂƉƐŬŽƌ^ŚĂƌƉ Ϭ͕Ϭϰϯ Ϭ͕Ϯϵϵ

DISKUSI

<ĂƌĂŬƚĞƌŝƐƟŬƐƵďũĞŬƉĞŶĞůŝƟĂŶ

^ĞďĂŶǇĂŬϴϳйƐƵďũĞŬƉĞŶĞůŝƟĂŶĂĚĂůĂŚƉĞƌĞŵƉƵĂŶ͕ ŚĂůŝŶŝƐĞƐƵĂŝĚĞŶŐĂŶůŝƚĞƌĂƚƵƌĚŝŵĂŶĂƉƌĞǀĂůĞŶƐŝZƉĂĚĂ ƉĞƌĞŵƉƵĂŶϮ͕ϱŬĂůŝůĞďŝŚďĞƐĂƌĚŝďĂŶĚŝŶŐƉĂĚĂůĂŬŝͲůĂŬŝ͘ ZĞƌĂƚĂƵƐŝĂƐƵďũĞŬƉĂĚĂƉĞŶĞůŝƟĂŶŝŶŝĂĚĂůĂŚϰϴ͕ϲϭƚĂŚƵŶ

ǇĂŶŐ ũƵŐĂ ƐĞƐƵĂŝ ĚĞŶŐĂŶ ůŝƚĞƌĂƚƵƌ ǇĂŶŐ ŵĞŶǇĞďƵƚŬĂŶ ďĂŚǁĂ ƉƵŶĐĂŬ ŝŶƐŝĚĞŶ Z ƉĂĚĂ ĚĞŬĂĚĞ ŬĞͲϰ ĚĂŶ ŬĞͲϱ͘ ZĞƌĂƚĂŬĂĚĂƌDDWϵƉĂĚĂƉĞŶĞůŝƟĂŶŝŶŝĂĚĂůĂŚϭϬϰ͕ϴϮŶŐͬ ŵůǇĂŶŐůĞďŝŚƟŶŐŐŝĚĂƌŝŚĂƌŐĂŶŽƌŵĂůŬĂĚĂƌDDWͲϵǇĂŝƚƵ ϵ͕ϱͲϴϬ͕ϮŶŐͬŵů͕ŚĂůŝŶŝũƵŐĂƐĞƐƵĂŝĚĞŶŐĂŶƉĞŶĞůŝƟĂŶŚĂŶŐ z,ĞƚĂůĚŝdĂŝǁĂŶǇĂŶŐŵĞŶĚĂƉĂƚĂŬĂŶŬĂĚĂƌƉůĂƐŵĂDDWͲ ϮĚĂŶDDWͲϵƉĂĚĂƉĂƐŝĞŶZĚŝdĂŝǁĂŶƐĞĐĂƌĂďĞƌŵĂŬŶĂ ůĞďŝŚƟŶŐŐŝĚŝďĂŶĚŝŶŐƉŽƉƵůĂƐŝƐĞŚĂƚ͘

ZĞƌĂƚĂ ůĂũƵ ĞŶĚĂƉ ĚĂƌĂŚ ;>Ϳ ƐĞďĂŐĂŝ ƉĞŶĂŶĚĂ ŝŶŇĂŵĂƐŝƉĂĚĂƉĞŶĞůŝƟĂŶŝŶŝ ĂĚĂůĂŚϱϴ͕ϱŵŵͬũĂŵ͕ůĞďŝŚ ƟŶŐŐŝĚĂƌŝŶŝůĂŝŶŽƌŵĂůůĂũƵĞŶĚĂƉĚĂƌĂŚƐĞŵĞŶƚĂƌĂƌĞƌĂƚĂ ŬĂĚĂƌĨĂŬƚŽƌƌĞƵŵĂƚŽŝĚƉĂĚĂƉĞŶĞůŝƟĂŶŝŶŝĂĚĂůĂŚϱϳ͕ϭϯ /hͬŵů ũƵŐĂ ůĞďŝŚ ƟŶŐŐŝ ĚĂƌŝ ŶŝůĂŝĐƵƚͲŽīǇĂŝƚƵ ϭϱ /hͬŵů͘ ZĞƌĂƚĂ ůĂŵĂ ƐĂŬŝƚ ƉĂĚĂ ƐƵďũĞŬ ƉĞŶĞůŝƟĂŶ ĂĚĂůĂŚ ϰ͕ϴϯ ƚĂŚƵŶ ĚĞŶŐĂŶ ůĂŵĂ ƐĂŬŝƚ ŵŝŶŝŵĂů ĂĚĂůĂŚ ϭ ƚĂŚƵŶ ĚĂŶ ůĂŵĂƐĂŬŝƚŵĂŬƐŝŵĂůĂĚĂůĂŚϭϰƚĂŚƵŶŚĂůŝŶŝƐĞƐƵĂŝĚĞŶŐĂŶ ůŝƚĞƌĂƚƵƌ ǇĂŶŐ ŵĞŶǇĞďƵƚŬĂŶ ďĂŚǁĂ Z ĂĚĂůĂŚ ƉĞŶǇĂŬŝƚ ĂƵƚŽŝŵƵŶ ǇĂŶŐ ŬƌŽŶŝŬ ĚĞŶŐĂŶ ƉĞƌũĂůĂŶĂŶ ƉĞŶǇĂŬŝƚ ǇĂŶŐ ďĞƌǀĂƌŝĂƐŝ ĚĂƌŝinsidious͕ ƚƌĂŶƐŝĞŶƚ ŚŝŶŐŐĂself limited. ZĞƌĂƚĂ ũƵŵůĂŚ ƐĞŶĚŝ ŶǇĞƌŝ ƉĂĚĂ ƉĞŶĞůŝƟĂŶ ŝŶŝ ĂĚĂůĂŚ ϱ͕ϰϭ ĚĂŶ ƌĞƌĂƚĂ ũƵŵůĂŚ ƐĞŶĚŝǇĂŶŐ ďĞŶŐŬĂŬ ĂĚĂůĂŚ Ϯ͕ϱϰ ŚĂů ŝŶŝ ƐĞƐƵĂŝ ĚĞŶŐĂŶ Z ƐĞďĂŐĂŝ ƉĞŶǇĂŬŝƚ ĂƵƚŽŝŵƵŶ ĚĞŶŐĂŶjoint symptom ǇĂŶŐ ŵĞŶŽŶũŽů͘ Z ƵŵƵŵŶǇĂ

ŵĞŶǇĞƌĂŶŐ ďĞďĞƌĂƉĂ ƐĞŶĚŝ ƚĞƌƵƚĂŵĂ ƐĞŶĚŝͲƐĞŶĚŝ ŬĞĐŝů ƐĞƉĞƌƟmetacarpophalangealĂƚĂƵƉƌŽǆŝŵĂůŝŶƚĞƌƉŚĂůĂŶŐ

ŶĂŵƵŶƉĂĚĂďĞďĞƌĂƉĂŬĂƐƵƐŵĂŶŝĨĞƐƚĂƐŝZďŝƐĂďĞƌƵƉĂ ŵŽŶŽĂƌƚŚƌŝƟƐ͘ WĂĚĂ ƉĞŶĞůŝƟĂŶ ŝŶŝ ĚŝŐƵŶĂŬĂŶ ƌĂĚŝŽŐƌĂĮ ŵĂŶƵƐďŝůĂƚĞƌĂůĚĞŶŐĂŶƉĞƌƟŵďĂŶŐĂŶďĂŚǁĂĞƌŽƐŝůĞďŝŚ ŵƵĚĂŚ ĚŝǀŝƐƵĂůŝƐĂƐŝ ĚĂŶ ĚŝŝĚĞŶƟĮŬĂƐŝ ƉĂĚĂ ƐĞŶĚŝͲƐĞŶĚŝ ƚĂŶŐĂŶ ĚŝďĂŶĚŝŶŐ ƉĂĚĂ ƐĞŶĚŝͲƐĞŶĚŝ ďĞƐĂƌ ƐĞƉĞƌƟ ƉĂĚĂ ƐĞŶĚŝůƵƚƵƚ͘

ĂƌŝƉĞŵĞƌŝŬƐĂĂŶƌĂĚŝŽŐƌĂĮĚŝĚĂƉĂƚŬĂŶƌĞƌĂƚĂƐŬŽƌ ƉĞŶǇĞŵƉŝƚĂŶ ƐĞŶĚŝ ĂĚĂůĂŚ ϱ͕ϯϳ ŚĂů ŝŶŝ ƐĞƐƵĂŝ ĚĞŶŐĂŶ ƚĞŽƌŝ ǇĂŶŐ ŵĞŶǇĞďƵƚŬĂŶ ƉĞŶĞŵƵĂŶ ƌĂĚŝŽůŽŐŝ ǇĂŶŐ ŬŚĂƐ ƵŶƚƵŬZĂĚĂůĂŚƉĞŶǇĞŵƉŝƚĂŶĐĞůĂŚƐĞŶĚŝǇĂŶŐƐŝŵĞƚƌŝƐ͕ ǇĂŶŐ ƵŵƵŵŶǇĂ ŵƵŶĐƵů ĚĂůĂŵ ǁĂŬƚƵ ϲͲϭϮ ďƵůĂŶ ĚĂƌŝ ƉĞƌũĂůĂŶĂŶƉĞŶǇĂŬŝƚ͕ƉĞŶǇĞŵƉŝƚĂŶĐĞůĂŚƐĞŶĚŝŵĞƌƵƉĂŬĂŶ ƉĞŶĂŶĚĂ ŬĞƌƵƐĂŬĂŶ ĚĂƌŝ ŬĂƌƟůĂŐŽ ǇĂŶŐ ĚŝƐĞďĂďŬĂŶ ŽůĞŚ ĞŶǌŝŵͲĞŶǌŝŵ ǇĂŶŐ ŵĞƌƵƐĂŬ ŵĂƚƌŝŬƐ ĞŬƐƚƌĂƐĞůƵůĞƌ ƚƵůĂŶŐ ƌĂǁĂŶ ǇĂŶŐ ĚŝŚĂƐŝůŬĂŶ ŽůĞŚ ƐŝŶŽǀŝŽƐŝƚ ƉĂĚĂ ƉĂŶŶƵƐ ĚĂŶ ŬŽŶĚŽƐŝƚ ǇĂŶŐ ĚŝĂŬƟŅĂŶ ŽůĞŚ ƐŝƚŽŬŝŶ͕ ƐĞŵĞŶƚĂƌĂ ƌĞƌĂƚĂ ƐŬŽƌ ĞƌŽƐŝ ƚƵůĂŶŐ ĂĚĂůĂŚ ϯ͕ϱ ŚĂů ŝŶŝ ũƵŐĂ ƐĞƐƵĂŝ ĚĞŶŐĂŶ ƉĂƚŽĮƐŝŽůŽŐŝ Z ĚŝŵĂŶĂ ƉĂĚĂ Z ƚĞƌũĂĚŝ ŝŶŇĂŵĂƐŝ ƉĂĚĂ ƐĞŶĚŝ͕ ŽƐƚĞŽƉĞŶŝĂ ĚĂŶ ƌĞƐŽƌƉƐŝ ƚƵůĂŶŐ ůĞǁĂƚReceptor

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ĚĂůĂŵƉŽƐŝƐŝǀĞƌƟŬĂů͘16WĂĚĂƉĞŶĞůŝƟĂŶŝŶŝ>ŚĂŶǇĂĚŝŶŝůĂŝ

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ϴ͘ 'ƌƵďĞƌ>͕^Žƌďŝ͕&ƌĞŶĐŚ>͕DĂƌĐŚĞƐĞD:͕EƵĞǀŽ':͕<ĞǁZZ͕ ƌďĞŝƚ >͘DĂƌŬĞĚůǇ ĞůĞǀĂƚĞĚ ƐĞƌƵŵ DDWͲϵ ;ŐĞůĂƟŶĂƐĞ Ϳ ůĞǀĞůƐ ŝŶƌŚĞƵŵĂƚŽŝĚĂƌƚƌŝƟƐ͗ĂƉŽƚĞŶƟĂůůǇƵƐĞĨƵůůĂďŽƌĂƚŽƌǇŵĂƌŬĞƌ͘ůŝŶ /ŵŵƵŶŽů/ŵŵƵŶŽƉĂƚŚŽů͘ϭϵϵϲ͖ϳϴ͗ϭϲϭͲϳϭ͘

9. sŝƩĞĐŽƋ K͕ WŽƵƉůŝŶ ^͕ <ƌǌĂŶŽǁƐŬĂ <͕ :ŽƵĞŶͲĞĂĚĞƐ &͕ DĞŶĂƌĚ

:͕'ĂǇĞƚ͕ĞƚĂů͘ZŚĞƵŵĂƚŽŝĚĨĂĐƚŽƌŝƐƚŚĞƐƚƌŽŶŐĞƐƚƉƌĞĚŝĐƚŽƌŽĨ ƌĂĚŝŽůŽŐŝĐĂů ƉƌŽŐƌĞƐƐŝŽŶ ŽĨ ƌŚĞƵŵĂƚŽŝĚ ĂƌƚŚƌŝƟƐ ŝŶ Ă ƚŚƌĞĞͲǇĞĂƌ ƉƌŽƐƉĞĐƟǀĞƐƚƵĚǇŝŶĐŽŵŵƵŶŝƚǇͲƌĞĐƌƵŝƚĞĚƉĂƟĞŶƚƐ͘ZŚĞƵŵĂƚŽůŽŐǇ͘ ϮϬϬϯ͖ϰϮ͗ϵϯϬͲϰϲ͘

10. ZĂƵZ͕,ĞƌďŽƌŶ'͕DĞŶŶŝŶŐĞƌ,͕^ĂŶŐŚĂK͘ZĂĚŝŽŐƌĂƉŚŝĐŽƵƚĐŽŵĞ

ĂŌĞƌ ƚŚƌĞĞ ǇĞĂƌƐ ŽĨ ƉĂƟĞŶƚƐ ǁŝƚŚ ĞĂƌůǇ ĞƌŽƐŝǀĞ ƌŚĞƵŵĂƚŽŝĚ ĂƌƚŚƌŝƟƐ ƚƌĞĂƚĞĚ ǁŝƚŚ ŝŶƚƌĂŵƵƐĐƵůĂƌ ŵĞƚŚŽƚƌĞĂǆĂƚĞ Žƌ ƉĂƌĞŶƚĞƌĂů ŐŽůĚ͘ǆƚĞŶƐŝŽŶŽĨĂŽŶĞǇĞĂƌĚŽƵďůĞďůŝŶĚƐƚƵĚǇŝŶϭϳϰƉĂƟĞŶƚƐ͘ ZŚĞƵŵĂƚŽůŽŐǇ͘ϮϬϬϮ͖ϰϭ͗ϭϵϲͲϮϬϰ͘

11. >ŝŶĚƋǀŝƐƚ͕:ŽŶƐŽŶŶ<͕^ĂǆŶĞd͕ďĞƌŚĂƌĚƚ<͘ŽƵƌƐĞŽĨƌĂĚŝŽŐƌĂƉŚŝĐ

ĚĂŵĂŐĞŽǀĞƌϭϬǇĞĂƌƐŝŶĂĐŽŚŽƌƚǁŝƚŚĞĂƌůǇƌŚĞƵŵĂƚŽŝĚĂƌƚŚƌŝƟƐ͘ ŶŶZŚĞƵŵŝƐ͘ϮϬϬϯ:Ƶů͖ϲϮ;ϳͿ͗ϲϭϭͲϲ͘

12. DŝĐŚĂĞů d͕ YŝŶŐ :ƵŶ ͕ dŚŝĞŶŶƵ ,͕ ŶŶĞ ͕ ĞŶƚĞ d͕ >ĞŝĨ Z Ğƚ Ăů͘

DĂƚƌŝǆ DĞƚĂůůŽƉƌŽƚĞŝŶĂƐĞ ϵ ĂŶĚ sĂƐĐƵůĂƌ ŶĚŽƚŚĞůŝĂů 'ƌŽǁƚŚ &ĂĐƚŽƌ ĂƌĞ ĞƐƐĞŶƟĂů ĨŽƌ KƐƚĞŽĐůĂƐƚ ZĞĐƌƵŝƚŵĞŶƚ ŝŶƚŽ ĞǀĞůŽƉŝŶŐ >ŽŶŐŽŶĞƐ͘dŚĞ:ŽƵƌŶĂůŽĨĞůůŝŽůŽŐǇ͘ϮϬϬϬ͖ϭϱϭ͗ϴϳϵͲϴϴϵ͘ ϭϯ͘ ŵŝĂďůĞ E͕ dĂƚ ^<͕ >ĂũĞŶĞƵƐƐĞ ͕ ƵǀĂů E͕ WĞůůĞƟĞƌ :W͕ DĂƌƚĞůͲ

WĞůůĞƟĞƌ :͕ ŽŝůĞĂƵ ͘ WƌŽƚĞŝŶĂƐĞͲĂĐƟǀĂƚĞĚ ƌĞĐĞƉƚŽƌ ;WZͿͲ Ϯ ĂĐƟǀĂƟŽŶ ŝŵƉĂĐƚƐ ďŽŶĞ ƌĞƐŽƌƉƟǀĞ ƉƌŽƉĞƌƟĞƐ ŽĨ ŚƵŵĂŶ ŽƐƚĞŽĂƌƚŚƌŝƟĐƐƵďĐŽŶĚƌĂůďŽŶĞŽƐƚĞŽďůĂƐƚ͘ŽŶĞ͘ϮϬϬϵ͖ϰϰ͗ϭϭϰϯͲϱϬ͘

14. tĂůĚĞŶďƵƌŐ :͕ &ŝƌĞƐƚĞŝŶ '͘ ƉŝĚĞŵŝŽůŽŐǇ͕ WĂƚŚŽůŽŐǇ ĂŶĚ

WĂƚŚŽŐĞŶĞƐŝƐŽĨZŚĞƵŵĂƚŽŝĚƌƚŚƌŝƟƐŝŶWƌŝŵĞƌŽŶƚŚĞZŚĞƵŵĂƟĚ ŝƐĞĂƐĞ͘ϭϯth_{ĞĚŝƟŽŶ͘ϮϬϬϴ͖ϭϮϮͲϭϯϯ͘}

ϭϱ͘ yƵĞ,͕DĂĞĐŚ>͕^ĂŵďƌŽŽŬWE͕:ĂĐŬƐŽŶ:͘ŝīĞƌĞŶƟĂůƌĞŐƵůĂƟŽŶ ŽĨ ŵĂƚƌŝǆ ŵĞƚĂůůŽƉƌŽƚĞŝŶĂƐĞ Ϯ ĂŶĚ ŵĂƚƌŝǆ ŵĞƚĂůůŽƉƌŽƚĞŝŶĂƐĞ ϵ ďǇĂĐƟǀĂƚĞĚƉƌŽƚĞŝŶ͗ƌĞůĞǀĂŶĐĞƚŽŝŶŇĂŵŵĂƟŽŶŝŶƌŚĞƵŵĂƚŽŝĚ ĂƌƚŚƌŝƟƐ͘ƌƚŚƌŝƟƐZŚĞƵŵ͘ϮϬϬϭ͖ϱϲ͗ϮϴϲϰͲϳ͘

16. WĂƵůƵƐ,͕ƌĂŚŶ͘/ƐĞƌǇƚŚƌŽĐǇƚĞƐĞĚŝŵĞŶƚĂƟŽŶƌĂƚĞƚŚĞƉƌĞĨĞƌĂďůĞ

ŵĞĂƐƵƌĞ ŽĨ ƚŚĞ ĂĐƵƚĞ ƉŚĂƐĞ ƌĞƐƉŽŶƐĞ ŝŶ ƌŚĞƵŵĂƚŽŝĚ ĂƌƚŚƌŝƟƐ͍ : ZŚĞƵŵĂƚŽů͘ϮϬϬϰ͖ϯϭ͗ϴϯϴͲϰϬ͘

ϭϳ͘ DĂŬŝŶĞŶ ,͕ <ĂƵƟĂŝŶĞŶ ,͕ ,ĂŶŶŽŶĞŶ W͕ ^ŽŬŬĂ d͘ /Ɛ ^Ϯϴ ĂŶ ĂƉƉƌŽƉŝĂƚĞƚŽŽůƚŽĂƐƐĞƐƐƌĞŵŝƐƐŝŽŶŝŶƌŚĞƵŵĂƚŽŝĚĂƌƚŚƌŝƟƐ͍ŶŶ ZŚĞƵŵŝƐ͘ϮϬϬϱ͖ϲϰ͗ϭϰϭϬͲϯ͘