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Revisión sistemática

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Relative Remission and Low Disease Activity Rates of Tofacitinib, Baricitinib, Upadacitinib, and Filgotinib versus Methotrexate in Patients with Disease-Modifying Antirheumatic Drug-Naive Rheumatoid Arthritis.

Autores Lee YH , Song GG
Revista Pharmacology
Año 2023
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Este artículo incluye 4 Estudios primarios 4 Estudios primarios (4 referencias)

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BACKGROUND: The relative efficacy of Janus kinase (JAK) inhibitors in producing remission and low disease activity (LDA) states remains unknown since there are currently no trials that provide direct comparisons among JAK inhibitors in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA). OBJECTIVES: This study aimed to assess the relative remission and LDA rates of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) in DMARD-naive patients with RA. METHOD: We conducted Bayesian network meta-analysis and included information from direct and indirect comparisons from randomized controlled trials that examined remission (Disease Activity Score in 28 Joints using C-reactive protein level [DAS28-CRP] <2.6) and LDA (DAS28-CRP ≤ 3.2) produced by tofacitinib, baricitinib, upadacitinib, filgotinib monotherapy, and MTX in patients with DMARD-naive RA. RESULTS: Four randomized controlled trials, comprising 2,185 patients, met the inclusion criteria. This network meta-analysis showed that treatment with tofacitinib, baricitinib, upadacitinib, and filgotinib achieved a significantly higher remission rate than that with MTX (odds ratio [OR] = 4.13, 95% CI = 2.88-6.02; OR = 2.12, 95% CI = 1.17-4.13; OR = 1.95, 95% CI = 1.10-3.50; OR = 1.79, 95% CI = 1.27-3.53). The ranking probability based on the surface under the cumulative ranking curve indicated that upadacitinib 15 mg had the highest probability of achieving remission (SUCRA = 0.985), followed by tofacitinib 5 mg (SUCRA = 0.574), baricitinib 4 mg (SUCRA = 0.506), filgotinib 200 mg (SUCRA = 0.431), and MTX (SUCRA = 0.004). Moreover, treatment with tofacitinib, baricitinib, upadacitinib, and filgotinib achieved significantly higher LDA rate than that with MTX. The ranking probability for LDA was similar to that for remission; upadacitinib 15 mg had the highest probability of achieving LDA, followed by tofacitinib 5 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX. CONCLUSIONS: Upadacitinib seems to be one of most effective interventions for achieving remission and LDA in DMARD-naive patients with RA based on the comparative analysis, and there are differences in remission and LDA rates induced by different JAK inhibitors.

Revisión sistemática

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Comparative study of the efficacy and safety of tofacitinib, baricitinib, upadacitinib, and filgotinib versus methotrexate for disease-modifying antirheumatic drug-naïve patients with rheumatoid arthritis.

Autores Sung YK , Lee YH
Revista Zeitschrift fur Rheumatologie
Año 2021
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Este artículo incluye 4 Estudios primarios 4 Estudios primarios (4 referencias)

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An assessment of the relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) was performed in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA). We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) so as to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and MTX in DMARD-naïve RA patients. Four RCTs comprising 2185 patients met the inclusion criteria. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of achieving the American College of Rheumatology 20% (ACR20) response rate, followed by baricitinib 4 mg, tofacitinib 5 mg, filgotinib 200 mg, and MTX. Tofacitinib, baricitinib, upadacitinib, and filgotinib treatments achieved significantly higher ACR50 and ACR70 responses compared to MTX. Tofacitinib 5 mg had the highest probability of achieving the ACR50 and ACR70 response rates, followed by upadacitinib 15 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX. The safety analysis based on serious adverse events, adverse events (AEs), and withdrawals due to AEs revealed no statistically significant differences between the respective intervention groups. In conclusion, tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for DMARD-naïve RA patients, suggesting a difference in efficacy and safety among the different JAK inhibitors.

Revisión sistemática

No clasificado

Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a systematic literature research.

Revista RMD open
Año 2020
Enlaces Pubmed DOI PubMed Central

Este artículo incluye 82 Estudios primarios 78 Estudios primarios (82 referencias)

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OBJECTIVES: Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). METHODS: A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation. RESULTS: 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed. CONCLUSION: JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence.

Revisión sistemática

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Safety of Janus Kinase Inhibitors in Patients with Inflammatory Bowel Diseases or Other Immune-mediated Diseases: a Systematic Review and Meta-Analysis.

Revista Gastroenterology
Año 2020
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Este artículo incluye 77 Estudios primarios 78 Estudios primarios (77 referencias)

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BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990 through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these 82 were included in the final analysis, comprising 66159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of and serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared to patients given placebo or active comparator (relative risk 0.72; 95% CI, 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% CI, 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Revisión sistemática

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JAK kinase inhibitors and varicella zoster virus infection in patients with rheumatoid arthritis. Systematic review of the literature

Revista Ann. Rheum. Dis.
Año 2020
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Este artículo incluye 34 Estudios primarios 33 Estudios primarios (34 referencias)

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Background: Objectives: Objetive: To assess the incidence of Herpes Zoster (HZ) infection in patients with Rheumatoid Arthritis (RA) treated with JAKi. Methods: Method: We conducted a systematic literature review searching in Medline, Embase and Cochrane. The final date was set on December 31, 2019, and only articles in English were included. See the following terms: rheumatoid arthritis, herpes zoster and the different JAK kinase inhibitors studied: tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib and decernotinib. Conference abstract, case series and clinical practice records were excluded. Only phase II and phase III clinical trials were included, as well as extension studies, with the following criteria:-Patients diagnosed with RA according to the American College of Rheumatology Criteria and /or EULAR criteria.-Drugs evaluated: tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib or decernotinib, all of them compared with placebo.-Safety data on HZ infection. The search included a total of 2521 publications of which 504 were duplicated, leaving 2017. After screening by title and abstract 1874 studies that did not meet the criteria were eliminated and there were 143 fully reviewed. At the end 42 papers were included in the review. The main objective of our study was the number of HZ infections depending on the doses of the drug administered, as well as with placebo. Data collected from each study was: Author and year of publication of the study, study design and population included, number of patients treated, treatment administered and percentage of patients treated for HZ in each treatment arm. Results: Results: In clinical trials of these drugs, a greater number of opportunistic infections due to varicella zoster virus have been identified compared to placebo, which leads to the appearance of HZ. The role of different JAKs in the immune response may suggest differences in safety profiles between these drugs, which could have clinical implications. Therefore, we analyze the results separately for each JAKi. Tofacitinib Of the 14 selected works, 4 are phase II, 8 phase III and 2 extension studies. We observe that the incidence of HZ ranges between 1% and 11%, the latter being the case of the Wollenhaupt extension study with a data collection period of nine and a half years. It is remarkable that in some of the studies included in this review there was no case of HZ and in others this information was not even collected. Baricitinib Two phase II studies, 6 phase III studies and one extension study were analyzed, with an incidence of HZ between 1% and 9%, data similar to those obtained with tofacitinib. Upadacitinib. An incidence of HZ between 1% and 4% was observed according to the 6 clinical trials (two phase II studies and four phase III studies) published as clinical product development. Filgotinib Data similar to upadacitinib, with frequencies between 1% and 4% of HZ according to the studies (three phase II studies and one phase III study). Peficitinib The incidence of HZ ranged between 4% and 7.5% (three phase II studies, two phase III studies, and one extension study). Decernotinib There are only published three phase II trials, of short duration and with only four cases collected from HZ. Conclusion: Conclusions: Opportunistic HZ infection have been reported between 1% and 11% in JAKi clinical trials. The results of the included studies seem to suggest that selective JAK1 inhibitors (Upadacitinib and Filgotinib) develop HZ as a treatment complication less frequently than other JAKi, but more studies are needed to support this conclusion.

Revisión sistemática

No clasificado

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials.

Autores Xie W , Huang Y , Xiao S , Sun X , Fan Y , Zhang Z
Revista Annals of the rheumatic diseases
Año 2019
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Este artículo incluye 25 Estudios primarios 25 Estudios primarios (25 referencias)

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OBJECTIVES: To investigate the effect of Janus kinase inhibitors (Jakinibs) on cardiovascular risk in adult patients with rheumatoid arthritis (RA) via a meta-analysis of randomised controlled trials (RCTs). METHODS: PubMed, Embase and Cochrane library were thoroughly searched for RCTs reporting safety issues in patients with RA receiving Jakinibs, from inception to October 2018. The primary and secondary outcomes were all cardiovascular events (CVEs) and major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs). OR and 95% CI were calculated using the Mantel-Haenszel fixed-effect method. RESULTS: 26 RCTs randomising 11 799 patients were included. No significant difference was observed regarding all CVEs risk following Jakinibs usage in general (OR 1.04 (0.61 to 1.76), p = 0.89), tofacitinib (OR 0.63 (0.26 to 1.54), p = 0.31), baricitinib (OR 1.21 (0.51 to 2.83), p = 0.66), upadacitinib (OR 3.29 (0.59 to 18.44), p = 0.18), peficitinib (OR 0.43 (0.07 to 2.54), p = 0.35) or decernotinib (OR 1.12 (0.13 to 10.11), p = 0.92). Likewise, there was no significant difference for Jakinibs treatment overall regarding occurrence of MACEs (OR 0.80 (0.36 to 1.75), p = 0.57) or VTEs (OR 1.16 (0.48 to 2.81), p = 0.74). Dose-dependent impact of Jakinibs on the risks of all CVEs, MACEs and VTEs was not observed in tofacitinib (5 mg vs 10 mg), upadacitinib (15 mg vs 30 mg), whereas baricitinib at 2 mg was found to be safer than 4 mg in all CVEs incidence (OR 0.19 (0.04 to 0.88), p = 0.03). CONCLUSION: The existing evidence from RCTs indicated no significant change in cardiovascular risk for Jakinib-treated patients with RA in a short-term perspective, but postmarketing data are sorely needed to ascertain their cardiovascular safety, especially at the higher dose, due to increased risk of thromboembolism events for both tofacitinib and baricitinib at higher dosage.

Revisión sistemática

No clasificado

A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis.

Revista Rheumatology (Oxford, England)
Año 2019
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Este artículo incluye 21 Estudios primarios 21 Estudios primarios (21 referencias)

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OBJECTIVES: To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors. METHODS: We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach. RESULTS: Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates. CONCLUSION: The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk. SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero 2017 CRD4201707879.

Revisión sistemática

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Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis.

Revista Seminars in Arthritis and Rheumatism
Año 2017
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Este artículo incluye 7 Estudios primarios 7 Estudios primarios (7 referencias)

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OBJECTIVE: To summarize and compare the risks of malignancies accompanying biologic DMARDs (b-DMARDs) and tofacitinib in rheumatoid arthritis (RA) in randomized clinical trials (RCTs) and long-term extension studies (LTEs). METHODS: Articles in Medline, Embase, Cochrane Library, and the Web of Science dated from 2000 to February 2015. Selection criteria were as follows: (1) focus on RCTs or LTEs in RA; (2) treatment with b-DMARDs or tofacitinib; (3) data on malignancies; and (4) a minimum follow-up of 12 weeks. Data included publication details, study design, risk of bias, number and types of malignancies, and patient characteristics and treatments. DATA SYNTHESIS: Of 113 articles and one updated report that were meta-analyzed, overall malignancies in RCTs showed odds ratio (95% confidence intervals) of 1.01 (0.72, 1.42) for all TNF antagonists, 1.12 (0.33, 3.81) for abatacept, 0.54 (0.20, 1.50) for rituximab, 0.70 (0.20, 2.41) for tocilizumab, and 2.39 (0.50, 11.5) for tofacitinib. Network meta-analysis of overall malignancies showed odds ratio (95% predictive intervals) of 1.68 (0.48-5.92) for infliximab, 0.79 (0.44-1.40) for etanercept, 0.93 (0.43-2.03) for adalimumab, 0.87 (0.28-2.75) for certolizumab, 0.87 (0.39-1.95) for golimumab, 1.04 (0.32-3.32) for abatacept, 0.58 (0.21-1.56) for rituximab, 0.60 (0.16-2.28) for tocilizumab, and 1.15 (0.24-5.47) for tofacitinib. Marginal numerical differences in the incidence rate of solid and hematological malignancies and non-melanoma skin cancers appeared in LTEs. CONCLUSIONS: In RCTs, treatment of RA with b-DMARDs or tofacitinib does not increase the risk for malignancies. Generalizability of the differences in the rate of specific malignancies encountered in LTEs requires continuous pharmacovigilance of real-world patients.

Revisión sistemática

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Riesgo de efectos adversos graves de fármacos biológicos y específicos en pacientes con artritis reumatoide: un metaanálisis de revisión sistemática.

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Revista Rheumatology (Oxford, England)
Año 2017
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Este artículo incluye 117 Estudios primarios 117 Estudios primarios (117 referencias)

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OBJETIVOS: Determinar las posibles diferencias en los efectos adversos graves entre los 10 DMARD sintéticos biológicos y específicos (b / ts-DMARDs) actualmente aprobados para la AR. MÉTODOS: Revisión sistemática en bases de datos bibliográficas, registros de ensayos y sitios web de agencias reguladoras identificaron ensayos aleatorios de b / ts-DMARDs aprobados para RA. Se realizaron metanálisis de redes utilizando modelos de regresión de Poisson de efectos mixtos para calcular las proporciones de tasas de eventos adversos graves (SAE) y fallecimientos entre cada uno de los 10 fármacos y el control (es decir, ningún tratamiento b / ts-DMARD), basados ​​en sujetos experimentando una Evento en relación a persona-años. La confianza en las estimaciones se evaluó aplicando el enfoque de evaluación, desarrollo y evaluación de calificaciones (GRADE). Resultados Se incluyó un total de 117 ensayos (47 615 pacientes). Los EAE fueron más frecuentes con el certolizumab en comparación con el abatacept (proporción de la tasa = 1,58, IC del 95%: 1,18, 2,14), adalimumab (1,36, IC del 95%: 1,02, 1,81), etanercept (1,60, IC del 95%: 1,18, 2,17) Golimumab (1,45, IC del 95%: 1,00, 2,08), rituximab (1,63, IC del 95%: 1,16, 2,30), tofacitinib (1,44; IC del 95%: 1,03; 2,02) y control (1,45; IC del 95%: 1,13; ); Y tocilizumab en comparación con abatacept (1,30, IC del 95%: 1,03, 1,65), etanercept (1,31; IC del 95%: 1,04; 1,67) y rituximab (1,34, IC del 95%: 1,01; 1,78). Ninguna otra comparación fue estadísticamente significativa. La contabilidad de la duración del estudio confirmó nuestras conclusiones para un tratamiento de hasta 6 meses, pero no para el tratamiento a largo plazo (6-24 meses). No se encontraron diferencias en la mortalidad entre b / ts-DMARDs y control. Basándose en el enfoque de GRADE, la confianza en las estimaciones fue baja debido a la ausencia de ensayos de comparación directa e imprecisión en estimaciones indirectas. CONCLUSIÓN: A pesar de la baja confianza en las estimaciones, nuestro análisis encontró diferencias potenciales en las tasas de SAEs. Nuestros datos sugieren que se debe tener precaución al decidir entre los fármacos disponibles. NÚMERO DE REGISTRO DE LA REVISIÓN SISTEMÁTICA: PROSPERO CRD42014014842.

Revisión sistemática

No clasificado

Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis.

Revista Annals of the rheumatic diseases
Año 2017
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Este artículo incluye 25 Estudios primarios 19 Estudios primarios (25 referencias)

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OBJECTIVES: To perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA). METHODS: An SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs) (tofacitinib and baricitinib) in randomised clinical trials. RESULTS: For GCs, four studies were included in the SLR. Patients without poor prognostic factors experienced benefit when GCs were added to methotrexate (MTX). Lower doses of GCs were similar to higher doses. For csDMARDs, two new studies comparing MTX monotherapy with combination csDMARD were included in the SLR. In the tREACH trial at the end of 12 months no difference between the groups in disease activity, functional ability and radiographic progression was seen, using principles of tight control (treat-to-target). In the CareRA trial, combination therapy with csDMARDs was not superior to MTX monotherapy and monotherapy was better tolerated.For tsDMARDs, tofacitinib and baricitinib were shown to be more effective than placebo (MTX) in different patient populations. CONCLUSIONS: Addition of GCs to csDMARD therapy may be beneficial but the benefits should be balanced against the risk of toxicity. Under tight control conditions MTX monotherapy is not less effective than combination csDMARDs, but better tolerated. Tofacitinib and baricitinib are efficacious in patients with RA, including those with refractory disease.