{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T07:10:10Z","timestamp":1765609810959},"reference-count":55,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2018,2,1]],"date-time":"2018-02-01T00:00:00Z","timestamp":1517443200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["NRF-2017R1A2A2A05001402"],"award-info":[{"award-number":["NRF-2017R1A2A2A05001402"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuroscience"],"published-print":{"date-parts":[[2018,2]]},"DOI":"10.1016\/j.neuroscience.2017.12.031","type":"journal-article","created":{"date-parts":[[2017,12,28]],"date-time":"2017-12-28T12:55:54Z","timestamp":1514465754000},"page":"181-191","source":"Crossref","is-referenced-by-count":8,"special_numbering":"C","title":["Spinal Sigma-1 Receptor-mediated Dephosphorylation of Astrocytic Aromatase Plays a Key Role in Formalin-induced Inflammatory Nociception"],"prefix":"10.1016","volume":"372","author":[{"given":"Hoon-Seong","family":"Choi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi-Ji","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheu-Ran","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Branden A.","family":"Smeester","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvin J.","family":"Beitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jang-Hern","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"issue":"1","key":"10.1016\/j.neuroscience.2017.12.031_b0005","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1046\/j.1365-2826.2001.00598.x","article-title":"Rapid and reversible inhibition of brain aromatase activity","volume":"13","author":"Balthazart","year":"2001","journal-title":"J Neuroendocrinol"},{"issue":"8","key":"10.1016\/j.neuroscience.2017.12.031_b0010","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1046\/j.1460-9568.2003.02598.x","article-title":"Calcium-dependent phosphorylation processes control brain aromatase in quail","volume":"17","author":"Balthazart","year":"2003","journal-title":"Eur J Neurosci"},{"issue":"9","key":"10.1016\/j.neuroscience.2017.12.031_b0015","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/j.1365-2826.2005.01344.x","article-title":"Interactions between kinases and phosphatases in the rapid control of brain aromatase","volume":"17","author":"Balthazart","year":"2005","journal-title":"J Neuroendocrinol"},{"issue":"1","key":"10.1016\/j.neuroscience.2017.12.031_b0020","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1210\/en.2005-0845","article-title":"Rapid control of brain aromatase activity by glutamatergic inputs","volume":"147","author":"Balthazart","year":"2006","journal-title":"Endocrinology"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0025","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fendo.2011.00034","article-title":"Sex differences in brain aromatase activity: genomic and non-genomic controls","volume":"2","author":"Balthazart","year":"2011","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"10.1016\/j.neuroscience.2017.12.031_b0030","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1152\/physrev.1987.67.1.67","article-title":"Peripheral and spinal mechanisms of nociception","volume":"67","author":"Besson","year":"1987","journal-title":"Physiol Rev"},{"issue":"3","key":"10.1016\/j.neuroscience.2017.12.031_b0035","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1254\/jphs.12R13CP","article-title":"Crucial interactions between selective serotonin uptake inhibitors and sigma-1 receptor in heart failure","volume":"121","author":"Bhuiyan","year":"2013","journal-title":"J Pharmacol Sci"},{"issue":"7","key":"10.1016\/j.neuroscience.2017.12.031_b0040","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1210\/endo.141.7.7578","article-title":"An age-related ovarian phenotype in mice with targeted disruption of the Cyp 19 (aromatase) gene","volume":"141","author":"Britt","year":"2000","journal-title":"Endocrinology"},{"issue":"7","key":"10.1016\/j.neuroscience.2017.12.031_b0045","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1002\/glia.20647","article-title":"Calcium\/calcineurin signaling in primary cortical astrocyte cultures: Rcan1-4 and cyclooxygenase-2 as NFAT target genes","volume":"56","author":"Canellada","year":"2008","journal-title":"Glia"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0050","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4137\/JEN.S11268","article-title":"Rapid modulation of aromatase activity in the vertebrate brain","volume":"7","author":"Charlier","year":"2013","journal-title":"J Exp Neurosci"},{"issue":"12","key":"10.1016\/j.neuroscience.2017.12.031_b0055","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1248\/bpb.b16-00326","article-title":"Neuronal NOS activates spinal NADPH oxidase 2 contributing to central sigma-1 receptor-induced pain hypersensitivity in mice","volume":"39","author":"Choi","year":"2016","journal-title":"Biol Pharm Bull"},{"issue":"1","key":"10.1016\/j.neuroscience.2017.12.031_b0060","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1124\/mol.115.101170","article-title":"Biochemical pharmacology of the sigma-1 receptor","volume":"89","author":"Chu","year":"2016","journal-title":"Mol Pharmacol"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0065","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.pain.2007.09.028","article-title":"Modulation of pain by estrogens","volume":"132","author":"Craft","year":"2007","journal-title":"Pain"},{"issue":"12","key":"10.1016\/j.neuroscience.2017.12.031_b0070","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/S0959-8049(01)00155-1","article-title":"Effect of letrozole on the lipid profile in postmenopausal women with breast cancer","volume":"37","author":"Elisaf","year":"2001","journal-title":"Eur J Cancer"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0075","first-page":"263","article-title":"Aromatase (estrogen synthase) activity in the dorsal horn of the spinal cord: Functional implications","volume":"1007","author":"Evrard","year":"2003","journal-title":"Steroids Nervous System"},{"issue":"33","key":"10.1016\/j.neuroscience.2017.12.031_b0080","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1523\/JNEUROSCI.1638-04.2004","article-title":"Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons","volume":"24","author":"Evrard","year":"2004","journal-title":"J Neurosci"},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0085","doi-asserted-by":"crossref","first-page":"R291","DOI":"10.1152\/ajpregu.00930.2005","article-title":"Estrogen synthesis in the spinal dorsal horn: a new central mechanism for the hormonal regulation of pain","volume":"291","author":"Evrard","year":"2006","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"33","key":"10.1016\/j.neuroscience.2017.12.031_b0090","doi-asserted-by":"crossref","first-page":"8745","DOI":"10.1523\/JNEUROSCI.1002-07.2007","article-title":"Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals","volume":"27","author":"Fernandez","year":"2007","journal-title":"J Neurosci"},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0095","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/S0306-4522(98)00340-6","article-title":"Aromatase expression by astrocytes after brain injury: Implications for local estrogen formation in brain repair","volume":"89","author":"Garcia-Segura","year":"1999","journal-title":"Neuroscience"},{"issue":"11","key":"10.1016\/j.neuroscience.2017.12.031_b0100","doi-asserted-by":"crossref","first-page":"4341","DOI":"10.1210\/en.2014-1158","article-title":"Aromatase inhibition exacerbates pain and reactive gliosis in the dorsal horn of the spinal cord of female rats caused by spinothalamic tract injury","volume":"155","author":"Ghorbanpoor","year":"2014","journal-title":"Endocrinology"},{"issue":"3","key":"10.1016\/j.neuroscience.2017.12.031_b0105","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2007.08.036","article-title":"Sigma-1 receptor chaperones at the ER-Mitochondrion interface regulate Ca2+ signaling and cell survival","volume":"131","author":"Hayashi","year":"2007","journal-title":"Cell"},{"issue":"21","key":"10.1016\/j.neuroscience.2017.12.031_b0110","doi-asserted-by":"crossref","first-page":"4830","DOI":"10.1111\/febs.13021","article-title":"Post-translational dual regulation of cytochrome P450 aromatase at the catalytic and protein levels by phosphorylation\/dephosphorylation","volume":"281","author":"Hayashi","year":"2014","journal-title":"Febs J"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0115","unstructured":"Health USNIo (1985). Laboratory animal welfare: Public Health Service policy on humane care and use of laboratory animals by awardee institutions; notice. Fed Regist 50(90): 19584-19585."},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0120","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1460-9568.2006.04913.x","article-title":"Estrogen controls PKC epsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons","volume":"24","author":"Hucho","year":"2006","journal-title":"Eur J Neurosci"},{"issue":"2\u20133","key":"10.1016\/j.neuroscience.2017.12.031_b0125","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0014-2999(80)90515-4","article-title":"Intrathecal morphine in mice: a new technique","volume":"67","author":"Hylden","year":"1980","journal-title":"Eur J Pharmacol"},{"issue":"5","key":"10.1016\/j.neuroscience.2017.12.031_b0130","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.pain.2011.01.046","article-title":"Spinal estrogen receptor alpha mediates estradiol-induced pronociception in a visceral pain model in the rat","volume":"152","author":"Ji","year":"2011","journal-title":"Pain"},{"issue":"4","key":"10.1016\/j.neuroscience.2017.12.031_b0135","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/sj.bjp.0706764","article-title":"Intrathecal treatment with \u03c31 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice","volume":"148","author":"Kim","year":"2006","journal-title":"Br J Pharmacol"},{"issue":"1","key":"10.1016\/j.neuroscience.2017.12.031_b0140","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0165-0173(96)00002-1","article-title":"A review of brain aromatase cytochrome P450","volume":"22","author":"Lephart","year":"1996","journal-title":"Brain Res Rev"},{"issue":"5","key":"10.1016\/j.neuroscience.2017.12.031_b0145","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/ana.22274","article-title":"Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease","volume":"68","author":"Luty","year":"2010","journal-title":"Ann Neurol"},{"issue":"1\u20133","key":"10.1016\/j.neuroscience.2017.12.031_b0150","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jsbmb.2008.09.001","article-title":"Aromatase is phosphorylated in situ at serine-118","volume":"112","author":"Miller","year":"2008","journal-title":"J Steroid Biochem"},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0155","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1124\/jpet.103.053447","article-title":"Protein kinase C-dependent potentiation of intracellular calcium influx by sigma(1) receptor agonists in rat hippocampal neurons","volume":"307","author":"Monnet","year":"2003","journal-title":"J Pharmacol Exp Ther"},{"issue":"24","key":"10.1016\/j.neuroscience.2017.12.031_b0160","doi-asserted-by":"crossref","first-page":"5881","DOI":"10.1111\/bph.12893","article-title":"Sigma 1 receptors activate astrocytes via p38 MAPK phosphorylation leading to the development of mechanical allodynia in a mouse model of neuropathic pain","volume":"171","author":"Moon","year":"2014","journal-title":"Br J Pharmacol"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0165","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.neuroscience.2015.06.009","article-title":"Colocalization of aromatase in spinal cord astrocytes: differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor","volume":"301","author":"O'Brien","year":"2015","journal-title":"Neuroscience"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0170","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.nbd.2013.10.010","article-title":"Neuroprotective effects of the Sigma-1 receptor (SIR) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation","volume":"62","author":"Peviani","year":"2014","journal-title":"Neurobiol Dis"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0175","doi-asserted-by":"crossref","DOI":"10.1155\/2016\/9802086","article-title":"Aromatase expression in the hippocampus of AD patients and 5xFAD mice","author":"Prange-Kiel","year":"2016","journal-title":"Neural Plast"},{"issue":"5","key":"10.1016\/j.neuroscience.2017.12.031_b0180","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S0197-0186(00)00105-4","article-title":"Cyclosporin A-sensitive signaling pathway involving calcineurin regulates survival of reactive astrocytes","volume":"38","author":"Pyrzynska","year":"2001","journal-title":"Neurochem Int"},{"issue":"8","key":"10.1016\/j.neuroscience.2017.12.031_b0185","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1111\/j.1476-5381.2011.01316.x","article-title":"Spinal neuronal NOS activation mediates sigma-1 receptor-induced mechanical and thermal hypersensitivity in mice: involvement of PKC-dependent GluN1 phosphorylation","volume":"163","author":"Roh","year":"2011","journal-title":"Br J Pharmacol"},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0190","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/glia.20910","article-title":"Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons","volume":"58","author":"Schaeffer","year":"2010","journal-title":"Glia"},{"issue":"11","key":"10.1016\/j.neuroscience.2017.12.031_b0195","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1210\/endo.142.11.8547","article-title":"Minireview: aromatase and the regulation of estrogen biosynthesis \u2013 some new perspectives","volume":"142","author":"Simpson","year":"2001","journal-title":"Endocrinology"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0200","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.neuroscience.2016.03.030","article-title":"The relationship of bone-tumor-induced spinal cord astrocyte activation and aromatase expression to mechanical hyperalgesia and cold hypersensitivity in intact female and ovariectomized mice","volume":"324","author":"Smeester","year":"2016","journal-title":"Neuroscience"},{"issue":"4","key":"10.1016\/j.neuroscience.2017.12.031_b0205","doi-asserted-by":"crossref","first-page":"E309","DOI":"10.36076\/ppj.2009\/12\/E09","article-title":"Calcineurin as a nociceptor modulator","volume":"12","author":"Smith","year":"2009","journal-title":"Pain Physician"},{"issue":"3","key":"10.1016\/j.neuroscience.2017.12.031_b0210","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0090451","article-title":"Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors alpha and beta, and androgen receptors","volume":"9","author":"Stanic","year":"2014","journal-title":"PLoS ONE"},{"issue":"12","key":"10.1016\/j.neuroscience.2017.12.031_b0215","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.tips.2010.08.007","article-title":"The sigma-1 receptor chaperone as an inter-organelle signaling modulator","volume":"31","author":"Su","year":"2010","journal-title":"Trends Pharmacol Sci"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0220","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.brainresbull.2017.05.016","article-title":"Characterization of aromatase expression in the spinal cord of an animal model of familial ALS","volume":"132","author":"Sun","year":"2017","journal-title":"Brain Res Bull"},{"issue":"7","key":"10.1016\/j.neuroscience.2017.12.031_b0225","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/sj.bjp.0702960","article-title":"Evidence for the involvement of spinal endogenous ATP and P2X receptors in nociceptive responses caused by formalin and capsaicin in mice","volume":"128","author":"Tsuda","year":"1999","journal-title":"Br J Pharmacol"},{"issue":"4","key":"10.1016\/j.neuroscience.2017.12.031_b0230","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.aquatox.2010.06.009","article-title":"17 alpha-Ethinylestradiol disrupts the ontogeny of the forebrain GnRH system and the expression of brain aromatase during early development of zebrafish","volume":"99","author":"Vosges","year":"2010","journal-title":"Aquat Toxicol"},{"issue":"6","key":"10.1016\/j.neuroscience.2017.12.031_b0235","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1211\/jpp.59.6.0006","article-title":"Pharmacokinetics of letrozole in male and female rats: influence of complexation with hydroxybutenyl-\u03b2-cyclodextrin","volume":"59","author":"Wempe","year":"2007","journal-title":"J Pharm Pharmacol"},{"issue":"3","key":"10.1016\/j.neuroscience.2017.12.031_b0240","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1111\/j.1471-4159.2006.04133.x","article-title":"Glutamate-stimulated ATP release from spinal cord astrocytes is potentiated by substance P","volume":"99","author":"Werry","year":"2006","journal-title":"J Neurochem"},{"key":"10.1016\/j.neuroscience.2017.12.031_b0245","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1146\/annurev.pharmtox.47.120505.105219","article-title":"Acute effects of estrogen on neuronal physiology","volume":"47","author":"Woolley","year":"2007","journal-title":"Annu Rev Pharmacol"},{"issue":"6","key":"10.1016\/j.neuroscience.2017.12.031_b0250","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.jpain.2012.03.005","article-title":"Hippocampal nerve growth factor potentiated by 17 beta-estradiol and involved in allodynia of inflamed TMJ in rat","volume":"13","author":"Wu","year":"2012","journal-title":"J Pain"},{"issue":"10","key":"10.1016\/j.neuroscience.2017.12.031_b0255","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1007\/s00213-014-3809-6","article-title":"Sigma 1 receptor activation regulates brain-derived neurotrophic factor through NR2A-CaMKIV-TORC1 pathway to rescue the impairment of learning and memory induced by brain ischaemia\/reperfusion","volume":"232","author":"Xu","year":"2015","journal-title":"Psychopharmacology"},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0260","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.neuroscience.2005.11.054","article-title":"Aromatase expression in the human temporal cortex","volume":"138","author":"Yague","year":"2006","journal-title":"Neuroscience"},{"issue":"1","key":"10.1016\/j.neuroscience.2017.12.031_b9000","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1097\/00000542-199801000-00023","article-title":"Comparison of the effects of treatment with intrathecal lidocaine given before and after formalin on both nociception and Fos expression in the spinal cord dorsal horn","volume":"88","author":"Yashpal","year":"1998","journal-title":"Anesthesiology"},{"issue":"1\u20132","key":"10.1016\/j.neuroscience.2017.12.031_b0265","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0006-8993(02)03895-7","article-title":"Simultaneous recordings of wind-up of paired spinal dorsal horn nociceptive neuron and nociceptive flexion reflex in rats","volume":"960","author":"You","year":"2003","journal-title":"Brain Res."},{"issue":"2","key":"10.1016\/j.neuroscience.2017.12.031_b0270","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","article-title":"Ethical guidelines for investigations of experimental pain in conscious animals","volume":"16","author":"Zimmermann","year":"1983","journal-title":"Pain"}],"container-title":["Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0306452217309211?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0306452217309211?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T08:41:43Z","timestamp":1660207303000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0306452217309211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2]]},"references-count":55,"alternative-id":["S0306452217309211"],"URL":"https:\/\/doi.org\/10.1016\/j.neuroscience.2017.12.031","relation":{},"ISSN":["0306-4522"],"issn-type":[{"value":"0306-4522","type":"print"}],"subject":[],"published":{"date-parts":[[2018,2]]}}}