The Role of the Autonomic Nervous System in Epilepsy and Migraine: A Narrative Review.

Autonomic symptoms may be local and general clinical manifestations of both epilepsy and migraine caused by the dysfunction of brain areas best known as the central autonomic network. Despite their prevalence, autonomic signs are often misdiagnosed and their treatment is undervalued. This review aims to describe the autonomic manifestations reported during seizures and migraineur attacks according to their presentation, focusing on the role of the central autonomic network (CAN) and on the parasympathetic outflow that often-induced cranial autonomic symptoms (CAS) during migraineur attacks. Further, our purpose is to analyze the pathophysiological meanings and whether their presence influences the prognosis and therapy of these disorders.

Prolactin and oxytocin: potential targets for migraine treatment.

Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.

Assessing the outcomes of parasacral transcutaneous electrical nerve stimulation (PTENS) in the treatment of enuresis in children: A systematic review and meta-analysis of randomized control trials.

INTRODUCTION: Nocturnal enuresis (NE) is a common pathology in children that can have significant behavioral, emotional, and social impacts on a child's life. Recent studies have assessed PTENS as a potential treatment method for NE, particularly in those who do not respond to initial first-line treatments. Literature has shown varying results with regard to its success. There has been no systematic review and meta-analysis to date assessing outcomes following this treatment. OBJECTIVES: Despite multiple studies showing the potential benefits of PTENS in NE, there has been no consensus regarding its efficacy. The aim of this study was to systematically analyze the effects of PTENS on children with NE. STUDY DESIGN: In September 2021, a search of PubMed, Embase and the Cochrane Library was carried out for studies relating to outcomes following PTENS in children with NE. Studies included were original publication English language randomized controlled trial (RCT's) with at least ten children receiving parasacral transcutaneous electrical nerve stimulation (PTENS). After assessing for relevant studies, data were collated and analyzed from the included studies. Risk of bias was assessed using the Cochrane seven domain assessment. Our primary outcome was response and nonresponse to treatment. These results were combined in a fixed effects meta-analysis model to obtain an overall estimate of the success rate. Information regarding demographics was also collected. There was no external funding for this review. RESULTS: Of 145 studies found initially, four RCT's (208 children) were included. The weighted mean rate of full response to active PTENS was 10.8% (0%-19%). All studies considered, meta-analysis showed no difference between PTENS and controls (RR: 0.70, 95% confidence interval [CI: 0.37-1.32]). Subgroup analysis of monosymptomatic enuresis showed no effect of PTENS compared to controls (RR = 0.58, 95% CI: [0.24-1.42]). When grouped, studies comparing PTENS to sham/behavioral treatment showed no benefit compared to controls (RR = 0.81, 95% CI: [0.05-12.53]) and those comparing PTENS to biofeedback/interferential current (IFC) showed no difference to controls (RR = 0.69, 95% CI: [0.36-1.33]). There was no evidence of a difference between cases and controls between these latter subgroups (RR = 0.70, 95% CI: [0.37-1.32]). DISCUSSION/CONCLUSION: Our results suggest that PTENS has no clear benefit in the management of children with NE compared to controls. Subgroup analysis showed that its use in monosymptomatic NE has no clear advantage. However, this review has highlighted the need for further high quality studies. Limitations to this review included a relatively small sample size and the use of prior or concomitant therapies.

A multinational survey on the management of the urinary tract in newborns with spina bifida: Are we following current EAU/ESPU guidelines?

AIMS: In August 2019, the European Association of Urology (EAU) and European Society for Paediatric Urology (ESPU) published updated guidelines on the management of neurogenic bladder in children and adolescents. Our study aimed to establish whether members of the ESPU are adhering to these guidelines. METHODS: We designed a survey comprising 26 questions using SurveyMonkey®. Respondents were asked about management of neurogenic bladder at birth in newborns with spina bifida (SB), urological investigations, as well as short and long-term follow-up in their institutions. RESULTS: There were 103 respondents to the survey (754 recipients, giving a response rate of 14%) spanning 36 countries. 100% of respondents carry out a renal/bladder ultrasound at birth. Only 53% routinely commence clean intermittent catheterization soon after birth as recommended by the guidelines. Only 56% recommend anticholinergic medications after abnormal videourodynamics (VUDs). The guidelines recommend the use of continued antibiotic prophylaxis if there is evidence of vesicoureteral reflux and hostile bladder/non-conclusive results on VUDs which is followed by only 30% of providers. 63% of respondents carry out baseline VUDs at the recommended time. Seeing larger volumes of SB patients, having a formal SB protocol, having formal SB multidisciplinary clinics and working in a tertiary referral center did not make respondents more likely to adhere to guidelines. CONCLUSIONS: Our survey demonstrated that large variations from the EAU/ESPU guidelines exist in practice. The study confirms that further work is required across institutions and countries to implement these evidence-based recommendations for standardized practice.

Cranial Autonomic Symptoms and Migraine: What Relationship and What Meaning? A Review.

Cranial autonomic symptoms (CAS) have been usually associated with trigeminal autonomic cephalalgias (TAC's), however in the last few years several reports in adult and pediatric population have reported important presence of the CAS in migraine. Also several evidences experimentally show that the increased parasympathetic outflow can enhance the sensitization of nociceptive receptors involved in migraine. The presence of CAS suggests an activation of the trigeminal-autonomic reflex, probably related to an over-activation of the trigeminal afferent arm. For these reasons identifing and understanding of these symptoms in migraine may be important to help in the diagnosis and effective management. The purpose of this review is, analyzing the literature data, to discuss the prevalence of these CAS in migraine, the pathophysiological meaning in the pathogenesis of migraine and whether their presence influences the prognosis and therapy of migraine in adult and pediatric age.

A successful centre for translational paediatric surgical research.

The National Children's Research Centre (NCRC), the single largest paediatric research centre in Ireland, has been in existence for over 50 years and is located on the grounds of the largest children's hospital in Ireland; Children's Health Ireland at Crumlin. Professor Puri was appointed as the Director of the Research in 1989 and became President of the NCRC in 2009, a position he held until 2016. Professor Puri is one of the most cited paediatric surgical researchers in the world. His research work has been cited over 23,500 times in peer-reviewed articles with an h-index of 76 and i10-index of 494. The aim of this review is to analyse the most relevant areas of academic research at the NCRC, Dublin, during the years when Prof. Puri was Director/President of the NCRC. In addition, the relevant factors essential to create a successful paediatric surgical research centre will be discussed. A literature search using PubMed/Medline was carried out using the search terms "Prem Puri" over a 40-year period (1980-2020). Articles were analysed to identify the most significant research areas in the field of paediatric surgical research and the relevant laboratory and clinical findings. In addition, a separate analysis of successful funding and human factors, such as research fellows working at the NCRC, was also carried out. During the period under review, Professor Puri's team published 750 articles in peer-reviewed journals. Three main areas of research were reviewed with a total number of 391 articles: congenital diaphragmatic hernia (CDH) was the topic with the largest number of publications (153), followed by Hirschsprung's disease (HSCR) (144) and Vesicoureteral reflux (VUR) (94). Eighty research fellows, all paediatric surgeons, from 18 different countries were trained in basic science under the supervision of Professor Puri at the NCRC. Over the last three decades, the NCRC has been one of the most successful centres for paediatric surgical research in the world. The three areas of research with the largest number of publications were identified as CDH, HSCR and VUR. Various factors can explain the success of the NCRC: (a) the constant presence, for over 30 years, of a very successful paediatric surgeon leading the centre, (b) a multicultural laboratory with research fellows from all over the world and (c) grants of more than 15 million raised over the years, which guaranteed a constant flow of resources for laboratory research.

Comparing the outcomes of parasacral transcutaneous electrical nerve stimulation for the treatment of lower urinary tract dysfunction in children: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Despite published evidence in recent decades suggesting improvement in lower urinary tract symptoms (LUTS) with the use of parasacral transcutaneous electrical nerve stimulation (PTENS), no consensus guidelines for therapy exist. This study systematically reviews the literature to assess the effect of PTENS in children with LUTS. METHODS: A database search conducted up to December 2019 included Medline, EMBASE, and the Cochrane Library. From the literature review, 6 randomized controlled studies (234 participants) comparing PTENS and standard treatment (urotherapy/anticholinergics) were considered. From each study, the success rates were available for PTENS and the control group. The ratio of success rates was computed-that is, the risk ratio (RR) and the risk difference (RD). RESULTS: The overall success rate with PTENS was 1.92 times that of children undergoing standard urotherapy alone (RR: 1.92, 95% confidence interval [CI: 1.02, 3.61]) and 1.56 for those undergoing either urotherapy alone or with pharmacotherapy (anticholinergics; RR: 1.56, 95% CI [1.04, 2.40]). No difference in the success rate was found when PTENS was used in patients failing previous treatment (urotherapy and pharmacological therapy; RR: 0.175, 95% CI [0.02, 1.45]). CONCLUSIONS: Current evidence suggests that PTENS is beneficial in children with LUTS. The chance of success is 1.92 times that of children undergoing standard urotherapy. However, in children who have failed urotherapy and pharmacological therapy, PTENS monotherapy has a limited role and should be an adjunct. Literature shortcomings included small numbers of patients, differing inclusion criteria, and PTENS protocols. A need exists for quality multicenter randomized controlled trials to prove the efficacy of PTENS in children with LUTS.

Megaprepuce: a systematic review of a rare condition with a controversial surgical management.

Megaprepuce (MP) is a rare and challenging condition characterised by an excessive inner prepuce, paucity of penile skin and an extremely narrow phimotic ring. The aetiological factors leading to its development are poorly understood. A variety of surgical techniques have been described in the last 26 years mostly with small number of patients and short follow-up. It is also highly likely that some series have in the past included different variants of inconspicuous penis combining concealed penis, MP and webbed penis. This article is a systematic review of the literature on Megaprepuce; in particular the embryology, history, aetiology, and the surgical techniques available for the correction of this unique penile anomaly will be presented and discussed in this study.

Outcomes of detrusorectomy in neurogenic bladders: A systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aims to assess the outcomes of detrusorectomy in children with neurogenic bladder (NB). MATERIALS AND METHODS: A search was performed in PUBMED, EMBASE and the Cochrane Library database in August 2023. The following search terms were used: "detrusorectomy", "detrusorotomy", "auto-augmentation". The two main primary outcomes were improvement in bladder capacity and bladder compliance after intervention. Outcomes were dichotomized into favorable and unfavorable. The secondary outcomes were the effect of postoperative bladder cycling on bladder compliance and bladder capacity and complications. RESULTS: 258 references were screened for inclusion, of these 242 were excluded. 8 of the remaining 16 studies were included for the qualitative and quantitative analysis. All studies were retrospective case series studies (165 patients). Median follow-up time varied between studies (1.75-11.1 years), while two studies reported a mean follow-up time of 8.1 years. Using a random effects meta-analysis, the overall rate for unchanged or improved bladder capacity was 95% (Proportion[CI]: 0.95 [0.61; 1.00]). The overall rate for improved bladder compliance after detrusorectomy was 67% (Proportion[CI]: 0.67 [0.26; 0.92)) (Summary Fig). In the bladder cycling group improved compliance was found in 89% of patients (Proportion[CI]: 0.89 [0.41; 0.99]), whereas it was 21% in the non-cycling group (Proportion[CI]: 0.21 [0.04; 0.61]) (p = 0.0552). Bladder cycling did not affect bladder capacity as the overall rate for unchanged or improved bladder capacity was 98% (Proportion[CI]: 0.98 [0.35; 0.92]) in the cycling and 73% (Proportion[CI]: 0.73 [0.46; 0.90]) in the non-cycling group (p > 0.05). Overall complications were encountered in 16 (9.7%) patients, with major complications (stones, bladder perforations) detected only in 5(3%) patients. DISCUSSION: Detrusorectomy leads to an improved bladder compliance in 67% of children. As such, detrusorectomy proves to be a viable procedure to enhance bladder compliance or to cure overactivity. Importantly, the beneficial effect of detrusorectomy on bladder compliance seems to be long-lasting. Bladder capacity remained unchanged or improved in almost all patients undergoing detrusorectomy. Postoperative bladder cycling was effective in improving bladder compliance outcome compared to the non-cycling group. Proper patient selection is the key to good postoperative outcomes. CONCLUSIONS: Detrusorectomy enhances bladder compliance in pediatric neurogenic bladders. Postoperative bladder cycling improves bladder compliance and the overall complication rate of the procedure is low. Therefore, detrusorectomy should be considered a valuable therapeutic option in the comprehensive management of neurogenic bladders in children.

Elevating pediatric urology care: The crucial role of nursing research in quality improvement.

This educational article highlights the critical role of pediatric urology nursing research in improving the care of children with urological conditions. It discusses the multifaceted nature of pediatric urology nursing, addresses challenges such as limited nurse scientists and resource constraints, and highlights the need to overcome barriers to increase research involvement. The authors emphasize the importance of prioritizing research areas, the promotion of collaboration, and the provision of adequate funding and academic time for pediatric nurses to contribute to evidence-based practice, to improve patient outcomes. Furthermore, it highlights the importance of research in advancing nursing practice, shaping protocols, and advocating for the rights and needs of children with urological conditions and their families.

Prenatal Nutritional Factors and Neurodevelopmental Disorders: A Narrative Review.

According to the DSM-5, neurodevelopmental disorders represent a group of heterogeneous conditions, with onset during the developmental period, characterized by an alteration of communication and social skills, learning, adaptive behavior, executive functions, and psychomotor skills. These deficits determine an impairment of personal, social, scholastic, or occupational functioning. Neurodevelopmental disorders are characterized by an increased incidence and a multifactorial etiology, including genetic and environmental components. Data largely explain the role of genetic and environmental factors, also through epigenetic modifications such as DNA methylation and miRNA. Despite genetic factors, nutritional factors also play a significant role in the pathophysiology of these disorders, both in the prenatal and postnatal period, underscoring that the control of modifiable factors could decrease the incidence of neurodevelopmental disorders. The preventive role of nutrition is widely studied as regards many chronic diseases, such as diabetes, hypertension, and cancer, but actually we also know the effects of nutrition on embryonic brain development and the influence of prenatal and preconceptional nutrition in predisposition to various pathologies. These factors are not limited only to a correct caloric intake and a good BMI, but rather to an adequate and balanced intake of macro and micronutrients, the type of diet, and other elements such as exposure to heavy metals. This review represents an analysis of the literature as regards the physiopathological mechanisms by which food influences our state of health, especially in the age of development (from birth to adolescence), through prenatal and preconceptional changes, underlying how controlling these nutritional factors should improve mothers' nutritional state to significantly reduce the risk of neurodevelopmental disorders in offspring. We searched key words such as "maternal nutrition and neurodevelopmental disorders" on Pubmed and Google Scholar, selecting the main reviews and excluding individual cases. Therefore, nutrigenetics and nutrigenomics teach us the importance of personalized nutrition for good health. So future perspectives may include well-established reference values in order to determine the correct nutritional intake of mothers through food and integration.

ERN eUROGEN Guidelines on the Management of Anorectal Malformations, Part IV: Organization of Care and Communication between Providers.

INTRODUCTION: Being born with an anorectal malformation (ARM) can have profound and lifelong implications for patients and parents. Organization of care and communication between health care providers is an overlooked area of patient care. The European Reference Network eUROGEN for rare and complex urogenital conditions assembled a panel of experts to address these challenges and develop comprehensive guidelines for the management of ARM. METHODS: The Dutch Quality Standard for ARM served as the basis for the development of guidelines. Literature was searched in Medline, Embase, and Cochrane. The ADAPTE method was utilized to incorporate the newest available evidence. A panel of 15 experts from seven European countries assessed currency, acceptability, and applicability of recommendations. Recommendations from the Dutch Quality Standard were adapted, adopted, or rejected and recommendations were formed considering all available evidence, expert consensus, and the European context. RESULTS: Aspects pertaining to organization of care, patient/parent/health care provider communication, and referral and collaboration between providers caring for ARM patients were assessed. Two new studies were identified. In total, the panel adapted 12 recommendations, adopted 7, and developed 2 de novo. The overall level of newly found evidence was considered low and most recommendations were based on expert opinion. CONCLUSION: Collaborative care and organization of care are gaining importance in the field of ARM. This guideline gives practical guidance on how to achieve better communication and collaboration between all involved parties, applicable at the European level.

ERN eUROGEN Guidelines on the Management of Anorectal Malformations Part I: Diagnostics.

INTRODUCTION: Anorectal malformations (ARMs) are rare congenital anomalies that involve the anus, rectum, and oftentimes the genitourinary tract. The management of ARM patients is complex, and many controversies exist. To address this issue, the European Reference Network eUROGEN for rare and complex urogenital conditions aimed to develop comprehensive guidelines for the management of ARM. METHODS: The Dutch Quality Standard for ARM served as the basis for the development of guidelines applicable on a European level. Literature was searched in Medline, Embase, and Cochrane. The ADAPTE method was utilized to incorporate the newest available evidence. A panel of 15 experts from 7 European countries assessed currency, acceptability, and applicability of recommendations. Recommendations from the Dutch Quality Standard were adapted, adopted, or rejected, and recommendations were formed considering current evidence and/or expert consensus. RESULTS: Prenatal and neonatal diagnostic workup as well as postsurgical follow-up of anorectal, genitourinary tract, and neurologic system were reviewed. Seven new studies were identified. The panel adapted 13 recommendations, adopted 7, and developed 8 de novo. The availability of high-quality evidence was limited, and most recommendations were based on retrospective studies, case series, or expert opinion. CONCLUSION: Patients with ARM and their families require highly specialized and comprehensive care from the prenatal period to adulthood. This guideline provides recommendations for a comprehensive diagnostic workup of children with ARM throughout their life that is applicable on a European level.

European Reference Network eUROGEN Guidelines on the Management of Anorectal Malformations, Part II: Treatment.

INTRODUCTION: Anorectal malformations (ARMs) are rare birth defects affecting the anorectum and oftentimes the genitourinary region. The management of ARM patients is complex and requires highly specialized surgical and medical care. The European Reference Network eUROGEN for rare and complex urogenital conditions aimed to develop comprehensive guidelines for the management of ARM applicable on a European level. METHODS: The Dutch Quality Standard for ARM served as the basis for the development of guidelines. Literature was searched in Medline, Embase, and Cochrane. The ADAPTE method was utilized to incorporate the newest available evidence. A panel of 15 experts from seven European countries assessed currency, acceptability, and applicability of recommendations. Recommendations from the Dutch Quality Standard were adapted, adopted, or rejected and recommendations were formed considering the current evidence, expert opinion, and the European context. RESULTS: Surgical and medical treatment of ARM, postoperative instructions, toilet training, and management of fecal and urinary incontinence were addressed. Seven new studies were identified. The panel adapted 23 recommendations, adopted 3, and developed 8 de novo. The overall level of newly found evidence was considered low. CONCLUSION: Treatment of ARM patients requires a multidisciplinary team and expertise about anatomical and surgical aspects of the disease, as well as long-term follow-up. This guideline offers recommendations for surgical and medical treatment of ARM and associated complications, according to the best available evidence and applicable on a European level.

ERN eUROGEN Guidelines on the Management of Anorectal Malformations Part III: Lifelong Follow-up and Transition of Care.

INTRODUCTION: Anorectal malformations (ARMs) are complex congenital anomalies of the anorectal region, oftentimes also affecting the genitourinary system. Although successful surgical correction can often be achieved in the neonatal period, many children will experience functional problems in the long term. The European Reference Network for rare and complex urogenital conditions (eUROGEN) assembled a panel of experts to address these challenges and develop comprehensive guidelines for the management of ARM. METHODS: The Dutch Quality Standard for ARM served as the foundation for the development of guidelines applicable on a European level. Literature was searched in Medline, Embase, and Cochrane. The ADAPTE method was utilized to incorporate the newest available evidence. A panel of 15 experts from 7 European countries assessed currency, acceptability, and applicability of recommendations. Recommendations from the Dutch Quality Standard were adapted, adopted, or rejected and recommendations were formed considering the current evidence and/or expert consensus. RESULTS: Lifelong follow-up, integration, and transition of care were assessed. A total of eight new studies were identified. The panel adapted 18 recommendations, adopted 6, and developed 6 de novo. Overall, the level of evidence was considered low. CONCLUSION: Successful lifelong follow-up and transition of care require a dedicated team of pediatric and adult specialist and an individually tailored patient-centered approach. This guideline summarizes the best available evidence on follow-up of ARM patients and provides guidance for the development of structured transition programs.

The importance of animal specificity in animal experimentation, part I: Anatomy in relation to pediatric urology.

Why and when is animal experimentation relevant? The answer to this question depends on the research question. In this short educational article we aim to raise awareness of the importance of formulating a very specific research question before choosing an animal species. An awareness of anatomical and physiological differences vis-a-vis similarities between species, will increase the potential for obtaining data that is relevant for translation to human conditions.

The importance of animal specificity in animal experimentation, part II: Physiological challenges and opportunities in relation to pediatric urology.

When performing animal experimentation in Pediatric Urology studies, it is important to be aware of physiological differences between species and to understand when relevant disease models are available. Diseased animal models may be more relevant in many cases, rather than performing studies in healthy and normally developed animals. For example, they may be more appropriate for the study of congenital malformations, to investigate the secondary effects of prenatal urinary obstruction, to study the effect of prenatal exposure to endogenous or exogenous factors which may lead to disease, or in testing bioengineered structures. In this short educational article, we aim to describe some disease models that have been used to simulate human pathologies and how, if properly designed, these studies can lead to important new knowledge for human translation. In addition, we also highlight the importance of formulating a research question(s) before deciding on the animal experimental model and species to choose.

Increased occurrence of disorders of sex development, prematurity and intrauterine growth restriction in children with proximal hypospadias associated with undescended testes.

PURPOSE: Proximal hypospadias represents 20% of hypospadias cases, which are considered to have a higher incidence of associated urological, nonurological, developmental and sexual development disorders, and chromosomal anomalies. We compared associated anomalies in boys with proximal hypospadias and undescended testis with those in boys with proximal hypospadias and descended testes. MATERIALS AND METHODS: We reviewed the medical records of 69 boys who underwent 2-stage hypospadias repair for proximal hypospadias at a single institution during the 11-year period of 2001 to 2011. Collected data included demographics, birth history, associated urological and extra-urological anomalies, karyotype analysis and gonad palpability. Patients were divided into group 1-those with proximal hypospadias and undescended testis, and group 2-those with proximal hypospadias and descended testes. Statistical analysis was performed using the 2-tailed Fisher exact test. RESULTS: There were 17 patients (25%) in group 1 with a median age of 2.2 years and 52 in group 2 (75%) with a median age of 2 years. Children in group 1 had a higher incidence of XY nondysgenetic testicular sexual development disorder (8 vs 11, p = 0.06), premature birth (9 vs 10, p = 0.01) and intrauterine growth restriction (8 each) than children in group 2 (p = 0.01). CONCLUSIONS: Prematurity and intrauterine growth restriction are significantly associated with proximal hypospadias and undescended testis. Also, due to the 28% incidence of an underlying sexual development disorder, male infants with proximal hypospadias should undergo multidisciplinary evaluation.