[et_pb_section fb_built=”1″ _builder_version=”3.22.7″ custom_padding=”||3px|||”][et_pb_row _builder_version=”3.25″][et_pb_column type=”4_4″ _builder_version=”3.25″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.6.6″ custom_padding=”12px|||||”]<\/p>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section][et_pb_section fb_built=”1″ specialty=”on” _builder_version=”3.22.3″ custom_padding=”24px|0px|25px|0px|false|false”][et_pb_column type=”3_4″ specialty_columns=”3″ _builder_version=”3.25″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_row_inner _builder_version=”3.25″][et_pb_column_inner saved_specialty_column_type=”3_4″ _builder_version=”3.25″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_blurb title=”Editoral in Hungarian” url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/szerk_bek_honlapra.pdf” url_new_window=”on” image=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/04\/pdf.png” icon_placement=”left” image_max_width=”105%” content_max_width=”1100px” _builder_version=”4.6.6″ header_font=”||||||||” header_font_size=”17px” header_line_height=”1.3em” body_font=”||on||||||” body_line_height=”1.3em” link_option_url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/szerk_bek_honlapra.pdf” link_option_url_new_window=”on”]<\/p>\n
Laz\u00e1ry Judit<\/p>\n
[\/et_pb_blurb][et_pb_toggle title=”Abstract” closed_toggle_text_color=”#000000″ closed_toggle_background_color=”rgba(0,0,0,0)” icon_color=”#0c71c3″ _builder_version=”3.22.7″ title_font=”|600|||||||” title_letter_spacing=”1px” text_orientation=”justified” custom_padding=”0px||10px” border_width_all=”0px” border_width_bottom=”1px”]<\/p>\n
Laz\u00e1ry Judit<\/p>\n<\/div>\n
A Neuropsychopharmacologia Hungarica hagyom\u00e1nyos tematikus sz\u00e1m\u00e1nak szerkeszt\u00e9si felk\u00e9r\u00e9se megtisztel\u0151 \u00e9s egy\u00fattal komoly kih\u00edv\u00e1st jelent\u0151 feladat. A tudom\u00e1nyos output \u00e9s a kapcsol\u00f3d\u00f3 trendek napjainkban szinte k\u00f6vethetetlenu\u0308l dinamikusan halmoz\u00f3dnak, emellett a r\u00e9szteru\u0308letek rohamos mikroszk\u00f3piz\u00e1l\u00f3d\u00e1sa miatt egy-egy t\u00e9ma feldolgoz\u00e1sa aktualit\u00e1sveszt\u00e9s n\u00e9lku\u0308l k\u00e9ts\u00e9gtelenu\u0308l neh\u00e9z pr\u00f3bat\u00e9tel.
Tudom\u00e1nyos munk\u00e1m sor\u00e1n els\u0151sorban a pszichi\u00e1triai k\u00f3rfolyamatok h\u00e1tter\u00e9ben h\u00faz\u00f3d\u00f3 molekul\u00e1ris biol\u00f3giai mechanizmusokkal foglalkozom imm\u00e1ron 12 \u00e9ve, ez\u00e9rt a teru\u0308lethez kapcsol\u00f3d\u00f3 t\u00e9ma v\u00e1laszt\u00e1sa adott volt. \u00c9s b\u00e1r a pszichogenomika egzakt, j\u00f3l k\u00f6ru\u0308lhat\u00e1rolt teru\u0308letnek t\u0171nhet els\u0151 hall\u00e1sra, az egyes k\u00e9ziratok \u00e1tolvas\u00e1sa sor\u00e1n azzal a tanuls\u00e1ggal szembesu\u0308lhet az olvas\u00f3, hogy a pszichogenomika mint diszciplina rendk\u00edvu\u0308l diverz teru\u0308lett\u00e9 v\u00e1lt mind a m\u00e9r\u00e9si m\u00f3dszereket, mind az asszoci\u00e1ci\u00f3s elemz\u00e9sek vizsg\u00e1lati elrendez\u00e9s\u00e9t, mind pedig a fenot\u00edpust tekintve. Emellett szembet\u0171n\u0151 lehet az is, hogy a pszichogenomika \u00e9s a biomarker kutat\u00e1s m\u00e1ra megkeru\u0308lhetetlenn\u00e9 v\u00e1lt a pszich\u00e9s zavarok tudom\u00e1nyos t\u00e1rgyal\u00e1sa sor\u00e1n, bele\u00e9rtve a patomechanizmus, a ter\u00e1pi\u00e1s indik\u00e1ci\u00f3, a ter\u00e1pi\u00e1s v\u00e1lasz, a mell\u00e9khat\u00e1sprofil, s\u0151t a placebo-reszponders\u00e9g k\u00e9rd\u00e9sk\u00f6r\u00e9t is. Ezzel \u00f6sszhangban aktu\u00e1lis sz\u00e1munkban besz\u00e1mol\u00f3 olvashat\u00f3 az endokannabinoid, a szerotonerg \u00e9s a kolinerg rendszer genetikai, valamint a vaszkul\u00e1ris endoteli\u00e1lis n\u00f6veked\u00e9si faktorral mint biomarkerrel kapcsolatos eredm\u00e9nyekr\u0151l a szorong\u00e1sra val\u00f3 hajlam, a depresszi\u00f3 farmakol\u00f3giai kezel\u00e9s\u00e9re adott v\u00e1lasz, valamint nikotin megvon\u00e1si tu\u0308netek eset\u00e9ben; emellett k\u00f6zl\u00e9sre keru\u0308l a \u2013 szint\u00e9n genetikai vonatkoz\u00e1sokat is t\u00e1rgyal\u00f3 \u2013 \u00e1ttekint\u0151 tanulm\u00e1ny, amely a placebo-hat\u00e1s pszichobiol\u00f3giai h\u00e1tter\u00e9vel kapcsolatos eredm\u00e9nyeket foglalja \u00f6ssze.<\/p>\n<\/div>\n
[\/et_pb_toggle][et_pb_blurb title=”Genetic association analyses of the endocannabinoid system on anxious phenotype” url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/lazary_eredeti_honlapra.pdf” url_new_window=”on” image=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/04\/pdf.png” icon_placement=”left” image_max_width=”105%” content_max_width=”1100px” _builder_version=”4.6.6″ header_font=”||||||||” header_font_size=”17px” header_line_height=”1.3em” body_font=”||on||||||” body_line_height=”1.3em” link_option_url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/lazary_eredeti_honlapra.pdf” link_option_url_new_window=”on”]<\/p>\n
Judit, Laz\u00e1ry , N\u00f3ra Eszl\u00e1ri , Gabriella Juh\u00e1sz and Gy\u00f6rgy Bagdy <\/p>\n
[\/et_pb_blurb][et_pb_toggle title=”Abstract” closed_toggle_text_color=”#000000″ closed_toggle_background_color=”rgba(0,0,0,0)” icon_color=”#0c71c3″ _builder_version=”4.6.6″ title_font=”|600|||||||” title_letter_spacing=”1px” text_orientation=”justified” custom_padding=”0px||10px” border_width_all=”0px” border_width_bottom=”1px”]Background: Accumulating data confirmed that the endocannabinoid system (ECS) is involved in the regulation of stress response and emotional processes, therefore ECS became
\nan important pharmacological target as a potential anxiolytic. Although unequivocal data
\nfrom animal studies confirmed the relevancy of the ECS in anxious phenotype, human genetic
\ndata are poorly available in the literature in this field. In the presented studies we tested possible associations between anxious phenotype and the cannabinoid receptor 1 and the fatty
\nacid amide hydrolase gene polymorphisms. Methods: Almost 900 subjects were involved in
\nour study from the general population. Anxious phenotype was measured by the State-Trait
\nAnxiety Inventory (STAI) and the anxious subscale of the Brief Symptom Inventory (BSI-ANX).
\nGenetic polymorphisms were genotyped from buccal mucosa samples\u2019 DNA by MassArray
\nSequenom technic. General linear models and post hoc tests were performed for statistical analyses. Results: Phenotypic variances were not dependent on single marker\u2019s effect.
\nHowever, interaction analyses provided significant results. Carriers of GG genotype of the
\nrs2180619 scored significantly higher on the STAI-T scale in presence of SS genotype of 5-HTTLPR compared to other allelic variants (p=0.0006). SS genotype together with GG genotype
\nmeant almost a 5-fold risk to be anxious (OR=4.64, 95% CI: 1.7-12.71). In case of the C385A
\npolymorphism of FAAH gene, A allele was associated with high scores of the BSI-ANX and
\nthe STAI-T if there were multiple childhood traumas in the anamnesis compared to C allele
\n(pinteract=0.00002; pinteract=0.0023; respectively). Conclusion: Our results confirmed earlier positive
\ndata on the association between ECS and anxious phenotype. According to our findings ECS
\nplays a significant role in the pathomechanism of anxious disorders by a complex mechanism
\nof genetic interaction with the serotonin transporter gene and childhood traumas.<\/p>\n
Keywords: anxiety, FAAH, early trauma, gene-environment interaction, endocannabinoid
\nsystem[\/et_pb_toggle][et_pb_blurb title=”Vascular endothelial growth factor (VEGF) as a potential biomarker in major depressive disorder” url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/elemery_eredeti_honlapra.pdf” url_new_window=”on” image=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/04\/pdf.png” icon_placement=”left” image_max_width=”105%” content_max_width=”1100px” _builder_version=”4.6.6″ header_font=”||||||||” header_font_size=”17px” header_line_height=”1.3em” body_font=”||on||||||” body_line_height=”1.3em” link_option_url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/elemery_eredeti_honlapra.pdf”]<\/p>\n
M\u00f3nika Elem\u00e9ry , Szilvia Kiss , X\u00e9nia Gonda , P\u00e9ter D\u00f6me and Judit Laz\u00e1ry <\/p>\n
[\/et_pb_blurb][et_pb_toggle title=”Abstract” closed_toggle_text_color=”#000000″ closed_toggle_background_color=”rgba(0,0,0,0)” icon_color=”#0c71c3″ _builder_version=”4.6.6″ title_font=”|600|||||||” title_letter_spacing=”1px” text_orientation=”justified” custom_padding=”0px||10px” border_width_all=”0px” border_width_bottom=”1px”]Background: There is growing evidence that vascular endothelial growth factor (VEGF) plays
\na crucial role in neurodevelopment and regeneration. Several data support that intact VEGF
\npathway is indispensable for therapeutic effect of antidepressants, any disruption of VEGF
\nsignaling can result treatment resistance. In our study we investigated the peripherial blood
\nVEGF level before and 4-week after antidepressant treatment in patients with major depressive
\nepisode and we compared VEGF levels between responders and non-responders. Methods:
\nWe recruited 34 patients diagnosed with major depression disorder rom our department.
\nDepressive symptoms were followed by the Montgomery Asberg Depression Scale. Level
\nof VEGF was measured from peripheral plasma by ELISA technic. For comparisons we performed general linear models and Mann-Whitney U tests. Results: Baseline VEGF level was
\nsignificantly higher in the non-responder subgroup compared to responders (p=0.017). In
\nregression analyses the baseline and end-point VEGF levels were correlated with end-point
\nMADRS (p=0.03; p=0.02, respectively). In our sample the higher baseline VEGF level was correlated with 2.75 times greater chance for treatment resistance in non-responders compared
\nto responders. Conclusion: Our results confirm the significant role of VEGF signaling in the
\npathomechanism of major depression disorder. These data suggest that high baseline VEGF
\nlevel can be a predictor for lack of therapy response, thus VEGF can be regarded as a potential
\nbiomarker for treatment resistance in major depression disorder.<\/p>\n
Keywords: biomarker, depression, VEGF, affective disorder, treatment resistant depression,
\ngrowth factor[\/et_pb_toggle][et_pb_blurb title=”Maternal bonding style, cholinergic receptor gene polymorphisms in association with smoking-related depressive symptoms” url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/csala_eredeti_honlapra.pdf” url_new_window=”on” image=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/04\/pdf.png” icon_placement=”left” image_max_width=”105%” content_max_width=”1100px” _builder_version=”4.6.6″ header_font=”||||||||” header_font_size=”17px” header_line_height=”1.3em” body_font=”||on||||||” body_line_height=”1.3em” link_option_url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/csala_eredeti_honlapra.pdf”]<\/p>\n
Ir\u00e9n Csala , P\u00e9ter D\u00f6me and Judit Laz\u00e1ry <\/p>\n
[\/et_pb_blurb][et_pb_toggle title=”Abstract” closed_toggle_text_color=”#000000″ closed_toggle_background_color=”rgba(0,0,0,0)” icon_color=”#0c71c3″ _builder_version=”4.6.6″ title_font=”|600|||||||” title_letter_spacing=”1px” text_orientation=”justified” custom_padding=”0px||10px” border_width_all=”0px” border_width_bottom=”1px”]Backgorund: There is accumulating evidence on the association between the cholinergic
\nsystem and nicotine dependence (ND) in the literature and the bidirectional relationship of ND
\nand depression. However, the molecular background of the development of ND and related
\naffective phenotype is not clear. Methods: We recruited 255 tretament-seeking smokers into
\nour study. For phenotyping assessments we used the Fagerstrom Nicotine Dependence Test;
\nThe Minnessotta Nicotine Withdrawal Scale; the Zung Self-Rating Depression Scale and the
\nParental Bonding Instrument. DNA was isolated from buccal mucosa sample and CHRNA4 and
\nCHRNB2 gene SNPs were genotyped with MassArray Sequenom techniques. For statistical
\nanalyses ANOVA test, Mann-Whitney U test, linear regression, two-step cluster analyses and
\nhapscore tests were performed. Results: Two-step cluster analysis revealed 3 well-differentiated
\nsubgroups among smokers based on phenotypic characteristics. One subgroup was associated with the highest withdrawal and depressive scores. Frequency of the risk haplotype
\nof CHRNA4 was significantly higher in this subgroup (p=0.019). Further, lifetime prevalence
\nof major depression was also significantly higher in this subgroup. Besides, CHRNB2 g\u00e9n variants showed a significant interacting effect with maternal bonding style on suicide thoughts
\n(p=0.005). Conclusions: Our results confirmed the genetic effect of CHRNA4 and CHRNB2 on
\nsmoking-related depression. These findings suggest that a genetically vulnerable subgroup
\ncan be distinguished among smokers and this subphenotype is more prone to withdrawal
\nand depressive symptoms. Our data suggest that suicidal risk depends on both CHRNB2 gene
\nvariants and maternal bonding style. Pharmacogenetic concerns of CHRNA4 and CHRNB2
\ngenes might be significant considering suicide as side effect of quitting therapy. Further
\npharmacogenetic investigations are requierd to clarify this possibility.<\/p>\n
Keywords: nicotine dependence, nicotine withdrawal symptoms, cholinergic genes, affective
\nwithdrawal symptoms, parental bonding style [\/et_pb_toggle][et_pb_blurb title=”Psychobiological background and clinical aspects of the placebo effect in psychiatry” url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/pogany_osszefoglkoz_honlapra.pdf” url_new_window=”on” image=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/04\/pdf.png” icon_placement=”left” image_max_width=”105%” content_max_width=”1100px” _builder_version=”4.6.6″ header_font=”||||||||” header_font_size=”17px” header_line_height=”1.3em” body_font=”||on||||||” body_line_height=”1.3em” link_option_url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/pogany_osszefoglkoz_honlapra.pdf”]<\/p>\n
L\u00e1szl\u00f3 Pog\u00e1ny <\/p>\n
[\/et_pb_blurb][et_pb_toggle title=”Abstract” closed_toggle_text_color=”#000000″ closed_toggle_background_color=”rgba(0,0,0,0)” icon_color=”#0c71c3″ _builder_version=”4.6.6″ title_font=”|600|||||||” title_letter_spacing=”1px” text_orientation=”justified” custom_padding=”0px||10px” border_width_all=”0px” border_width_bottom=”1px”]The placebo-effect is present in almost every field of medicine, however, in the assessment of
\nthe effect of psychotropic drugs it is a major problem. The rise of the placebo-effect in clinical trials is observed during the last decades, in spite of all efforts to introduce new methods
\nin clinical trials to overcome this problem and the number of studies aiming to unveil the
\nmechanisms that lie in the background that this phenomenon have risen. A considerable
\namount of data has accumulated regarding the psychobiological background of placeboeffect, however, the details of underlying mechanisms are still not clear. Furthermore, the
\nlack of objective tools for the assessment of the phenotypic changes during the treatment
\nof psychiatric disorders makes it even more difficult to differentiate the symptom intensity
\nchanges related to drug response from the placebo effect. The consequences of this scarcity
\nof information concerning the background of placebo-effect may hinder the development
\nof new compounds, having enormous medical, scientific and economical disadvantages. In
\nthis review we summarise the psychobiological mechanisms in the background of placebo
\neffect and its impact on clinical trials.<\/p>\n
Keywords: placebo, nocebo, psychotropic medicine trials, randomized clinical trials, compound
\nefficiency trials[\/et_pb_toggle][et_pb_blurb title=”From stone-craved genes to Michelangelo: significance and different aspects of gene-environment interaction” url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/lazary_osszefoglkoz_honlapra.pdf” url_new_window=”on” image=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/04\/pdf.png” icon_placement=”left” image_max_width=”105%” content_max_width=”1100px” _builder_version=”4.6.6″ header_font=”||||||||” header_font_size=”17px” header_line_height=”1.3em” body_font=”||on||||||” body_line_height=”1.3em” link_option_url=”https:\/\/mppt.hu\/magazin\/pdf\/xix-evfolyam-4-szam\/lazary_osszefoglkoz_honlapra.pdf”]<\/p>\n
Judit Laz\u00e1ry <\/p>\n
[\/et_pb_blurb][et_pb_toggle title=”Abstract” closed_toggle_text_color=”#000000″ closed_toggle_background_color=”rgba(0,0,0,0)” icon_color=”#0c71c3″ _builder_version=”4.6.6″ title_font=”|600|||||||” title_letter_spacing=”1px” text_orientation=”justified” custom_padding=”0px||10px” border_width_all=”0px” border_width_bottom=”1px”]Although genetic studies have improved a lot in recent years, without clinical relevance sometimes their significance is devalued. Reviewing the major milestones of psychogenomics it can
\nbe seen that break-through success is just a question of time. Investigations of direct effect
\nof genetic variants on phenotypes have not yielded positive findings. However, an important
\nstep was taken by adapting the gene-environment interaction model. In this model genetic
\nvulnerability stepped into the place of \u201cstone craved\u201d pathology. Further progress happened
\nwhen studies of environmental factors were combined with genetic function (epigenetics).
\nThis model provided the possibility for investigation of therapeutic interventions as environmental factors and it was proven that effective treatments exert a modifying effect on gene
\nexpression. Moreover, recent developments focus on therapeutic manipulation of gene function (e.g. chemogenetics). Instead of \u201cstone craved\u201d genes up-to-date dynamically interacting
\ngene function became the basis of psychogenomics in which correction of the expression
\nis a potential therapeutic tool. Keeping in mind these trends and developments, there is no
\ndoubt that genetics will be a fundamental part of daily clinical routine in the future.<\/p>\n
Keywords: psychogenomics, epigenomics, gene therapy, programmed development, personalized therapy[\/et_pb_toggle][\/et_pb_column_inner][\/et_pb_row_inner][\/et_pb_column][et_pb_column type=”1_4″ _builder_version=”3.25″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_image src=”https:\/\/mppt.hu\/wp-content\/uploads\/2019\/05\/b1_2017_dec_kicsi.jpg” align_tablet=”center” align_phone=”” align_last_edited=”on|desktop” _builder_version=”3.23″ box_shadow_style=”preset3″][\/et_pb_image][\/et_pb_column][\/et_pb_section]<\/p>\n","protected":false},"excerpt":{"rendered":"
VOLUME 19, ISSUE 4, DECEMBER 2017Laz\u00e1ry JuditSzerkeszt\u0151i bek\u00f6sz\u00f6nt\u0151 Laz\u00e1ry Judit A Neuropsychopharmacologia Hungarica hagyom\u00e1nyos tematikus sz\u00e1m\u00e1nak szerkeszt\u00e9si felk\u00e9r\u00e9se megtisztel\u0151 \u00e9s egy\u00fattal komoly kih\u00edv\u00e1st jelent\u0151 feladat. A tudom\u00e1nyos output \u00e9s a kapcsol\u00f3d\u00f3 trendek napjainkban szinte k\u00f6vethetetlenu\u0308l dinamikusan halmoz\u00f3dnak, emellett a r\u00e9szteru\u0308letek rohamos mikroszk\u00f3piz\u00e1l\u00f3d\u00e1sa miatt egy-egy t\u00e9ma feldolgoz\u00e1sa aktualit\u00e1sveszt\u00e9s n\u00e9lku\u0308l k\u00e9ts\u00e9gtelenu\u0308l neh\u00e9z pr\u00f3bat\u00e9tel.Tudom\u00e1nyos munk\u00e1m sor\u00e1n els\u0151sorban a […]<\/p>\n","protected":false},"author":4,"featured_media":48298,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":""},"project_category":[58],"project_tag":[],"class_list":["post-48522","project","type-project","status-publish","has-post-thumbnail","hentry","project_category-neuropsychopharmacologia-hungarica-3-en"],"_links":{"self":[{"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/project\/48522","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/project"}],"about":[{"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/types\/project"}],"author":[{"embeddable":true,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/comments?post=48522"}],"version-history":[{"count":8,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/project\/48522\/revisions"}],"predecessor-version":[{"id":49506,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/project\/48522\/revisions\/49506"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/media\/48298"}],"wp:attachment":[{"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/media?parent=48522"}],"wp:term":[{"taxonomy":"project_category","embeddable":true,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/project_category?post=48522"},{"taxonomy":"project_tag","embeddable":true,"href":"https:\/\/mppt.hu\/en\/wp-json\/wp\/v2\/project_tag?post=48522"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}