{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T18:16:10Z","timestamp":1788632170020,"version":"build-2803163510"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100018531","name":"Major Science and Technology Projects in Yunnan Province","doi-asserted-by":"publisher","award":["202202AG050013"],"award-info":[{"award-number":["202202AG050013"]}],"id":[{"id":"10.13039\/501100018531","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31860607"],"award-info":[{"award-number":["31860607"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008871","name":"Yunnan Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["202403AP140003"],"award-info":[{"award-number":["202403AP140003"]}],"id":[{"id":"10.13039\/501100008871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008871","name":"Yunnan Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["YNWR-QNBJ-2019-142"],"award-info":[{"award-number":["YNWR-QNBJ-2019-142"]}],"id":[{"id":"10.13039\/501100008871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1016\/j.ejmech.2025.118173","type":"journal-article","created":{"date-parts":[[2025,9,14]],"date-time":"2025-09-14T14:19:25Z","timestamp":1757859565000},"page":"118173","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"special_numbering":"C","title":["Design and function analysis of novel antimicrobial peptides derived from Cathelicidin-DM: Insights into structure-function relationships"],"prefix":"10.1016","volume":"300","author":[{"given":"Ying","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoqiang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanlin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9836-0252","authenticated-orcid":false,"given":"Yuzhu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"8","key":"10.1016\/j.ejmech.2025.118173_bib1","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1258\/jrsm.2009.09k036","article-title":"The introduction of 'chemotherapy' using arsphenamine - the first magic bullet","volume":"102","author":"Williams","year":"2009","journal-title":"J. R. Soc. Med."},{"issue":"28","key":"10.1016\/j.ejmech.2025.118173_bib2","article-title":"G. European survey on transatlantic task force on antimicrobial resistance action, targets for the reduction of antibiotic use in humans in the transatlantic taskforce on antimicrobial resistance (TATFAR) partner countries","volume":"24","author":"D'Atri","year":"2019","journal-title":"Euro Surveill."},{"key":"10.1016\/j.ejmech.2025.118173_bib3","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2020.112580","article-title":"Antimicrobial and anti-inflammatory activities of short dodecapeptides derived from duck cathelicidin: plausible mechanism of bactericidal action and endotoxin neutralization","volume":"204","author":"Kumar","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.118173_bib4","doi-asserted-by":"crossref","DOI":"10.1016\/j.chemosphere.2020.126351","article-title":"Occurrence and toxicity of antibiotics in the aquatic environment: a review","volume":"251","author":"Kovalakova","year":"2020","journal-title":"Chemosphere"},{"issue":"3","key":"10.1016\/j.ejmech.2025.118173_bib5","doi-asserted-by":"crossref","DOI":"10.1002\/psc.3294","article-title":"Multiple action mechanism and in vivo antimicrobial efficacy of antimicrobial peptide Jelleine-I","volume":"27","author":"Jia","year":"2021","journal-title":"J. Pept. Sci."},{"issue":"6","key":"10.1016\/j.ejmech.2025.118173_bib6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.3390\/ph7060723","article-title":"Antimicrobial peptides in reptiles","volume":"7","author":"van Hoek","year":"2014","journal-title":"Pharmaceuticals"},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib7","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s11658-024-00542-4","article-title":"The direct binding of bioactive peptide Andersonin-W1 to TLR4 expedites the healing of diabetic skin wounds","volume":"29","author":"Li","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"issue":"3","key":"10.1016\/j.ejmech.2025.118173_bib8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s12223-013-0280-4","article-title":"Plant antimicrobial peptides","volume":"59","author":"Nawrot","year":"2014","journal-title":"Folia Microbiol."},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib9","doi-asserted-by":"crossref","first-page":"7319","DOI":"10.1038\/s41467-024-51730-x","article-title":"Synergistic collaboration between AMPs and non-direct antimicrobial cationic peptides","volume":"15","author":"Ye","year":"2024","journal-title":"Nat. Commun."},{"issue":"6490","key":"10.1016\/j.ejmech.2025.118173_bib10","doi-asserted-by":"crossref","DOI":"10.1126\/science.aau5480","article-title":"Antimicrobial peptides: application informed by evolution","volume":"368","author":"Lazzaro","year":"2020","journal-title":"Science"},{"key":"10.1016\/j.ejmech.2025.118173_bib11","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2019.113746","article-title":"An active domain HF-18 derived from hagfish intestinal peptide effectively inhibited drug-resistant bacteria in vitro\/vivo","volume":"172","author":"Jiang","year":"2020","journal-title":"Biochem. Pharmacol."},{"issue":"10","key":"10.1016\/j.ejmech.2025.118173_bib12","doi-asserted-by":"crossref","DOI":"10.3390\/ijms23105463","article-title":"Amyloidogenic peptides: new class of antimicrobial peptides with the novel mechanism of activity","volume":"23","author":"Galzitskaya","year":"2022","journal-title":"Int. J. Mol. Sci."},{"issue":"3","key":"10.1016\/j.ejmech.2025.118173_bib13","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/med.21542","article-title":"Antimicrobial peptides: promising alternatives in the post feeding antibiotic era","volume":"39","author":"Wang","year":"2019","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.ejmech.2025.118173_bib14","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fchem.2019.00043","article-title":"Reassessing the host defense peptide landscape","volume":"7","author":"Haney","year":"2019","journal-title":"Front. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib15","doi-asserted-by":"crossref","DOI":"10.1111\/jfbc.12546","article-title":"Recent insights into structure-function relationships of antimicrobial peptides","volume":"43","author":"Ahmed","year":"2019","journal-title":"J. Food Biochem."},{"issue":"2","key":"10.1016\/j.ejmech.2025.118173_bib16","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1021\/acsabm.2c00767","article-title":"Design of fmoc-phenylalanine Nanofibrillar Hydrogel and Mechanistic studies of its antimicrobial action against both Gram-positive and gram-negative bacteria","volume":"6","author":"Sharma","year":"2023","journal-title":"ACS Appl. Bio Mater."},{"issue":"6","key":"10.1016\/j.ejmech.2025.118173_bib17","doi-asserted-by":"crossref","first-page":"6799","DOI":"10.1021\/acsami.3c16004","article-title":"Preventing E. coli biofilm formation with antimicrobial peptide-functionalized surface coatings: recognizing the dependence on the bacterial binding mode using live-cell microscopy","volume":"16","author":"Hansson","year":"2024","journal-title":"ACS Appl. Mater. Interfaces"},{"issue":"13","key":"10.1016\/j.ejmech.2025.118173_bib18","doi-asserted-by":"crossref","first-page":"16471","DOI":"10.1021\/acsami.3c00191","article-title":"Supramolecular hydrogels for precisely controlled antimicrobial peptide delivery for diabetic wound healing","volume":"15","author":"Jeong","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"issue":"11","key":"10.1016\/j.ejmech.2025.118173_bib19","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1021\/acsinfecdis.3c00289","article-title":"Confronting the threat: designing highly effective bis-benzimidazolium agents to overcome biofilm persistence and antimicrobial resistance","volume":"9","author":"Petit","year":"2023","journal-title":"ACS Infect. Dis."},{"issue":"8","key":"10.1016\/j.ejmech.2025.118173_bib20","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1021\/acsbiomaterials.3c00759","article-title":"Structure-activity relationship study of helix-stabilized antimicrobial peptides containing nonproteinogenic amino acids","volume":"9","author":"Ito","year":"2023","journal-title":"ACS Biomater. Sci. Eng."},{"issue":"16","key":"10.1016\/j.ejmech.2025.118173_bib21","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1021\/acs.jafc.6b00730","article-title":"Antibacterial effects of a cell-penetrating peptide isolated from kefir","volume":"64","author":"Miao","year":"2016","journal-title":"J. Agric. Food Chem."},{"issue":"18","key":"10.1016\/j.ejmech.2025.118173_bib22","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.1016\/j.jmb.2018.12.015","article-title":"Peptide design principles for antimicrobial applications","volume":"431","author":"Torres","year":"2019","journal-title":"J. Mol. Biol."},{"issue":"21","key":"10.1016\/j.ejmech.2025.118173_bib23","doi-asserted-by":"crossref","first-page":"19561","DOI":"10.1021\/acs.jmedchem.4c01855","article-title":"Development of \u03b1-helical antimicrobial peptides with imperfect amphipathicity for superior activity and selectivity","volume":"67","author":"Wu","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2025.118173_bib24","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2020.105276","article-title":"The revitalization of antimicrobial peptides in the resistance era","volume":"163","author":"Liu","year":"2021","journal-title":"Pharmacol. Res."},{"issue":"7","key":"10.1016\/j.ejmech.2025.118173_bib25","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.peptides.2008.02.019","article-title":"Structure-activity relations of parasin I, a histone H2A-derived antimicrobial peptide","volume":"29","author":"Koo","year":"2008","journal-title":"Peptides"},{"issue":"15","key":"10.1016\/j.ejmech.2025.118173_bib26","doi-asserted-by":"crossref","first-page":"4514","DOI":"10.1021\/ja068265m","article-title":"Alpha-helical peptide containing N,N-dimethyl lysine residues displays low-nanomolar and highly specific binding to RRE RNA","volume":"129","author":"Hyun","year":"2007","journal-title":"J. Am. Chem. Soc."},{"issue":"2","key":"10.1016\/j.ejmech.2025.118173_bib27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11274-015-1986-z","article-title":"Archetypal tryptophan-rich antimicrobial peptides: properties and applications","volume":"32","author":"Shagaghi","year":"2016","journal-title":"World J. Microbiol. Biotechnol."},{"issue":"16","key":"10.1016\/j.ejmech.2025.118173_bib28","doi-asserted-by":"crossref","first-page":"9301","DOI":"10.1021\/acsomega.0c00189","article-title":"Cathelicidin-DM is an antimicrobial peptide from duttaphrynus melanostictus and has wound-healing therapeutic potential","volume":"5","author":"Shi","year":"2020","journal-title":"ACS Omega"},{"issue":"6","key":"10.1016\/j.ejmech.2025.118173_bib29","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1002\/bip.21436","article-title":"Tryptophan residues: scarce in proteins but strong stabilizers of \u03b2-hairpin peptides","volume":"94","author":"Santiveri","year":"2010","journal-title":"Biopolymers"},{"issue":"8","key":"10.1016\/j.ejmech.2025.118173_bib30","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1093\/jac\/dky144","article-title":"Antibacterial activity and mechanism of action of analogues derived from the antimicrobial peptide mBjAMP1 isolated from Branchiostoma japonicum","volume":"73","author":"Park","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.peptides.2007.10.013","article-title":"Evaluation of the inhibitory effects of human serum components on bactericidal activity of human beta defensin 3","volume":"29","author":"Maisetta","year":"2008","journal-title":"Peptides"},{"issue":"21","key":"10.1016\/j.ejmech.2025.118173_bib32","doi-asserted-by":"crossref","DOI":"10.3390\/ijms232113316","article-title":"A novel antimicrobial peptide spampcin(56-86) from Scylla paramamosain exerting rapid bactericidal and anti-biofilm activity in vitro and anti-infection in vivo","volume":"23","author":"Jiang","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.ejmech.2025.118173_bib33","article-title":"Functional roles of aromatic residues and helices of papiliocin in its antimicrobial and anti-inflammatory activities","volume":"5","author":"Lee","year":"2015","journal-title":"Sci. Rep."},{"issue":"21","key":"10.1016\/j.ejmech.2025.118173_bib34","doi-asserted-by":"crossref","DOI":"10.3390\/ijms222111401","article-title":"Mechanism of antimicrobial peptides: antimicrobial, anti-inflammatory and antibiofilm activities","volume":"22","author":"Luo","year":"2021","journal-title":"Int. J. Mol. Sci."},{"issue":"8","key":"10.1016\/j.ejmech.2025.118173_bib35","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbamem.2020.183291","article-title":"Binding of an antimicrobial peptide to bacterial cells: interaction with different species, strains and cellular components","volume":"1862","author":"Savini","year":"2020","journal-title":"Biochim. Biophys. Acta Biomembr."},{"issue":"21","key":"10.1016\/j.ejmech.2025.118173_bib36","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.2174\/138161209788682325","article-title":"The roles of antimicrobial peptides in innate host defense","volume":"15","author":"Diamond","year":"2009","journal-title":"Curr. Pharm. Des."},{"issue":"11","key":"10.1016\/j.ejmech.2025.118173_bib37","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1021\/acsinfecdis.3c00316","article-title":"Tree frog-derived cathelicidin protects mice against bacterial infection through its antimicrobial and anti-inflammatory activities and regulatory effect on phagocytes","volume":"9","author":"He","year":"2023","journal-title":"ACS Infect. Dis."},{"issue":"15","key":"10.1016\/j.ejmech.2025.118173_bib38","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1021\/acs.jpcb.8b11496","article-title":"Molecular dynamics investigation into the effect of zinc(II) on the structure and membrane interactions of the antimicrobial peptide clavanin A","volume":"123","author":"Duay","year":"2019","journal-title":"J. Phys. Chem. B"},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib39","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13568-021-01229-1","article-title":"Melittin as a promising anti-protozoan peptide: current knowledge and future prospects","volume":"11","author":"Memariani","year":"2021","journal-title":"AMB Express"},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib40","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/med.21986","article-title":"Antioxidant peptides, the guardian of life from oxidative stress","volume":"44","author":"Zhu","year":"2024","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.ejmech.2025.118173_bib41","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2023.175941","article-title":"Cath-DM-NT, a peptide derived from the skin of Duttaphrynus melanostictus, shows dual lectin-like and antioxidant activity","volume":"956","author":"Xiong","year":"2023","journal-title":"Eur. J. Pharmacol."},{"issue":"3","key":"10.1016\/j.ejmech.2025.118173_bib42","doi-asserted-by":"crossref","DOI":"10.1590\/1414-431x20198186","article-title":"Rapid, specific, and sensitive detection of the ureR_1 gene in Klebsiella pneumoniae by loop-mediated isothermal amplification method","volume":"52","author":"Li","year":"2019","journal-title":"Braz. J. Med. Biol. Res."},{"issue":"4","key":"10.1016\/j.ejmech.2025.118173_bib43","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/iwj.13153","article-title":"Antimicrobial effects of local anaesthetics","volume":"16","author":"Kesici","year":"2019","journal-title":"Int. Wound J."},{"issue":"5","key":"10.1016\/j.ejmech.2025.118173_bib44","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/bip.20853","article-title":"Protein secondary structure analyses from circular dichroism spectroscopy: methods and reference databases","volume":"89","author":"Whitmore","year":"2008","journal-title":"Biopolymers"},{"key":"10.1016\/j.ejmech.2025.118173_bib45","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2019.111623","article-title":"The design of a cell-selective fowlicidin-1-derived peptide with both antimicrobial and anti-inflammatory activities","volume":"182","author":"Rajasekaran","year":"2019","journal-title":"Eur. J. Med. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2025.118173_bib46","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1186\/s13046-019-1354-1","article-title":"A novel asymmetrical anti-HER2\/CD3 bispecific antibody exhibits potent cytotoxicity for HER2-positive tumor cells","volume":"38","author":"Yu","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523425009389?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523425009389?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T01:01:57Z","timestamp":1773104517000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523425009389"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":46,"alternative-id":["S0223523425009389"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2025.118173","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Design and function analysis of novel antimicrobial peptides derived from Cathelicidin-DM: Insights into structure-function relationships","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2025.118173","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"118173"}}