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In our previous work, we reported alterations in protamines/histones ratio, in DNA binding of these proteins and their involvement in DNA oxidative damage in 84% of the young men living in the Land of Fires. In the present work, we extended our findings, evaluating any alterations in spermatozoa of a family case, a father and son, living in this area, to also give a first look at the possibility of transgenerational inherited effects of environmental contaminants on the molecular alterations of sperm nuclear basic proteins (SNBP), DNA and semen parameters. In the father and son, we found a diverse excess of copper and chromium in the semen, different alterations in SNBP content and low DNA binding affinity of these proteins. In addition, DNA damage, in the presence of CuCl2 and H2O2, increased by adding both the father and son SNBP. Interestingly, son SNBP, unlike his father, showed an unstable DNA binding and were able to produce DNA damage even without external addition of CuCl2, in line with a lower seminal antioxidant activity than the father. The peculiarity of some characteristics of son semen could be a basis for possible future studies on transgenerational effects of pollutants on fertility.

Mytilus galloprovincialis female specimens were collected from two mussel farms located in two sites next to Castel dell’Ovo, a historical complex located in the Naples Bay. Such sites were named, respectively, A‐area and B‐area for the different microbiological parameters so that mussels from A‐area can be sold without purification, whereas mussels from B‐area must be purified before sale. The mussels were collected during the nonreproductive (summer 2009) and reproductive periods (autumn 2009). Gonadosomatic index, structural organization of the ovary, presence of apoptosis, estrogen receptors expression, as well as the bisphenol A (BPA) content in the ovaries, were evaluated. Ovaries from specimens collected in area B showed a different and significant distribution of the investigated biomarkers as well as of BPA content in respect to those measured in the A‐area specimens, confirming that mussels are valid sentinel organisms to biomonitor in the Naples bay too.

The prevalence, correlates, and management of tobacco use disorder (TUD) or nicotine dependence (ND) among people with severe mental illness (SMI), namely schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), remain unclear. Therefore, a systematic review and meta-analysis was conducted. Electronic databases were systematically searched from inception to July 12, 2020, for observational studies documenting the prevalence, odds, and correlates of TUD/ND among people with SMI; randomized controlled trials (RCTs) informing the management of TUD/ND in people with SMI were also included. Random-effects meta-analyses were conducted. Sources of heterogeneity were explored. Nineteen observational studies, including 7527 participants with SMI met inclusion criteria. TUD/ND co-occurred in 33.4-65% of people with SMI. Rates were higher among males. While bupropion and varenicline represent promising treatment opportunities for schizophrenia with TUD/ND, non-pharmacological interventions require further research, mainly for people with primary mood disorders. TUD/ND represent prevalent co-occurring conditions among people with SMI. Further well-designed RCTs are warranted to inform their management.

Few longitudinal studies have so far investigated the impact of sustained COVID-19 among people with pre-existing psychiatric disorders. We conducted a prospective study involving people with serious mental illness (n = 114) and healthy controls (n = 41) to assess changes in the Perceived Stress Scale, Generalized Anxiety Disorder Scale, Patient Health Questionnaire, and Specific Psychotic Experiences Questionnaire scores 18 months after the COVID-19 pandemic outset. Subjects underwent interviews with a mental health professional in April 2020 and at the end of the local third wave (October 2021). A significant increase in perceived stress was found in healthy controls, especially females. Psychiatric patients showed a significant worsening of anxiety symptoms compared to baseline records (t = -2.3, p = 0.036). Patients who rejected vaccination had significantly higher paranoia scores compared to those willing to get vaccinated (U = 649.5, z = -2.02, p = 0.04). These findings indicate that COVID-19's sustained emergency may cause enduring consequences on mental health, soliciting further investigations.

SARS-CoV-2 has become one of the most studied viruses of the last century. It was assumed that the only possible host for these types of viruses was mammalian eukaryotic cells. Our recent studies show that microorganisms in the human gastrointestinal tract affect the severity of COVID-19 and for the first time provide indications that the virus might replicate in gut bacteria. In order to further support these findings, in the present work, cultures of bacteria from the human microbiome and SARS-CoV-2 were analyzed by electron and fluorescence microscopy. The images presented in this article, in association with the nitrogen (15N) isotope-labeled culture medium experiment, suggest that SARS-CoV-2 could also infect bacteria in the gut microbiota, indicating that SARS-CoV-2 could act as a bacteriophage. Our results add new knowledge to the understanding of the mechanisms of SARS-CoV-2 infection and fill gaps in the study of the interactions between SARS-CoV-2 and non-mammalian cells. These findings could be useful in suggesting specific new pharmacological solutions to support the vaccination campaign.

Mercury is one of the most dangerous environmental pollutants. In this work, we analysed the effects of exposure of Mytilus galloprovincialis to 1, 10 and 100 pM HgCl2 for 24 h on the gonadal morphology and on the expression level of three stress genes: mt10, hsp70 and πgst. In this tissue we also evaluated the level of steroidogenic enzymes 3β-HSD and 17β-HSD and the expression of PL protein genes. Finally, we determined difference in sperm chromatin accessibility to micrococcal nuclease. We found alterations in gonadal morphology especially after exposure to 10 and 100 pM HgCl2 and hypo-expression of the three stress genes, particularly for hsp70. Furthermore, decreased labelling with both 3β-HSD and 17β-HSD antibodies was observed following exposure to 1 and 10 pM HgCl2 and complete absence at 100 pM HgCl2 exposure. Gonads of mussels exposed to all HgCl2 doses showed decreased expression of PL protein genes especially for PLIII. Finally, micrococcal nuclease digestions showed that all doses of HgCl2 exposure resulted in increased sperm chromatin accessibility to this enzyme, indicative of improper sperm chromatin structure. All of these changes provide preliminary data of the potential toxicity of mercury on the reproductive health of this mussel.

This paper aims to investigate whether and how enterprise risk management (ERM) quality may be influenced by national culture. Using a sample of 105 banks from 21 countries over the period of 2013-2020, we document that power distance, masculinity, uncertainty avoidance and long-term orientation are significantly associated with ERM quality. Our research contributes to the existing risk literature by highlighting how the dimensions of national culture impact ERM quality. The article also discusses how the cultural dimensions of a national culture embedded in the organizational values can influence the quality of bank's risk management processes. This study helps banking regulators by providing a clear picture of how an informal institution, such as national culture, contributes to explaining differences in the quality of ERM implementation.

Introduction This work represents the continuation of the studies presented in two e-posters during the EPA 2021 conference (De Filippi et al., 2021; Rignanese et al., 2021), which addressed the physical pain-suicidality association (k=44 studies). Objectives The aim of this meta-analysis is to provide an update of those studies, integrating data relating to adolescents, adults, and olders. Methods We started with the analysis of three papers, in particular a meta-analysis (Calati et al., 2015) and two systematic reviews (Hinze et al., 2019; Santos et al., 2019). After searching on Pubmed (until September 2020), data were extracted from articles comparing the rates of current and lifetime suicidal thoughts and behaviours (death wish, suicidal ideation, suicidal planning, suicide attempt and suicide death: DW, SI, SP, SA, and SD) in adolescents, adults, and olders with any type of physical pain and in individuals who did not report this condition. Data were analysed using Comprehensive Meta-Analysis Software (CMA) version 2. Results 67 studies were included, of which 16 on adolescents, 29 on adults, 16 on olders, and 6 on mixed ages. Although quite high between-study heterogeneity was detected in most analyses, results suggested that individuals with physical pain are more likely to report any form of suicidal outcome if compared to those not affected by pain. Conclusions Collected data are therefore in line with previous literature on this topic, which considered physical pain an extremely predictive risk factor for suicidal thoughts and behaviours. However, further research on this topic would be extremely useful. Disclosure No significant relationships.

The purpose of this paper is to investigate whether the firms with the same Big Four audit firm and from the same legal system disclose more comparable non-GAAP measures. Using 23,436 pairs of European firms, we hand-collected infor-mation on the non-GAAP measures disclosed in the statement of comprehensive income. The results showed that the firms with the same Big Four audit firm or from the same legal system are positively and significantly associated with non-GAAP comparability. Our work adds to the studies on accounting comparability. Furthermore, it provides fresh insights that support the latest IASB activity on the Primary Financial Statement project, under which the standard setter has en-dorsed ED/2019/7 General Presentation and Disclosures.

Substance use disorder (SUD) is a common comorbidity in individuals with bipolar disorder (BD), and it is associated with a severe course of illness, making early identification of the risk factors for SUD in BD warranted. We aimed to identify, through machine-learning models, the factors associated with different types of SUD in BD. We recruited 508 individuals with BD from a specialized unit. Lifetime SUDs were defined according to the DSM criteria. Random forest (RF) models were trained to identify the presence of (i) any (SUD) in the total sample, (ii) alcohol use disorder (AUD) in the total sample, (iii) AUD co-occurrence with at least another SUD in the total sample (AUD+SUD), and (iv) any other SUD among BD patients with AUD. Relevant variables selected by the RFs were considered as independent variables in multiple logistic regressions to predict SUDs, adjusting for relevant covariates. AUD+SUD could be predicted in BD at an individual level with a sensitivity of 75% and a specificity of 75%. The presence of AUD+SUD was positively associated with having hypomania as the first affective episode (OR = 4.34 95% CI = 1.42–13.31), and the presence of hetero-aggressive behavior (OR = 3.15 95% CI = 1.48–6.74). Machine-learning models might be useful instruments to predict the risk of SUD in BD, but their efficacy is limited when considering socio-demographic or clinical factors alone.

BackgroundHomelessness has been associated with multiple detrimental health outcomes across observational studies. However, relatively few randomized controlled trials (RCTs) have been conducted on people who experience homelessness (PEH). Thus, this umbrella review ranked the credibility of evidence derived from systematic reviews (SRs) and meta-analyses (MAs) of observational studies investigating the associations between homelessness and any health outcome as well as RCTs targeting health needs in this population.MethodsSeveral databases were systematically searched from inception through April 28, 2021. Any SR and/or MA reporting quantitative data and providing a control group were eligible for inclusion. The credibility of the evidence derived from observational studies was appraised by considering the significance level of the association and the largest study, the degree of heterogeneity, the presence of small-study effects as well as excess significance bias. The credibility of evidence was then ranked in five classes. For SRs and/or MAs of RCTs, we considered the level of significance and whether the prediction interval crossed the null. The AMSTAR-2 and AMSTAR-plus instruments were adopted to further assess the methodological quality of SRs and/or MAs. The Newcastle-Ottawa Scale (NOS) was employed to further appraise the methodological quality of prospective cohort studies only; a sensitivity analysis limited to higher quality studies was conducted.ResultsOut of 1549 references, 8 MAs and 2 SRs were included. Among those considering observational studies, 23 unique associations were appraised. Twelve of them were statistically significant at thep≤0.005 level. Included cases had worst health-related outcomes than controls, but only two associations reached a priori-defined criteria for convincing (class I) evidence namely hospitalization due to any cause among PEH diagnosed with HIV infection, and the occurrence of falls within the past year among PEH. According to the AMSTAR-2 instrument, the methodological quality of all included SRs and/or MAs was “critically low.” Interventional studies were scant.ConclusionWhile homelessness has been repeatedly associated with detrimental health outcomes, only two associations met the criteria for convincing evidence. Furthermore, few RCTs were appraised by SRs and/or MAs. Our umbrella review also highlights the need to standardize definitions of homelessness to be incorporated by forthcoming studies to improve the external validity of the findings in this vulnerable population.

Parenthood age may affect the risk for the development of different psychiatric disorders in the offspring, including bipolar disorder (BD). The present systematic review and meta-analysis aimed to appraise the relationship between paternal age and risk for BD and to explore the eventual relationship between paternal age and age at onset of BD. We searched the MEDLINE, Scopus, Embase, PsycINFO online databases for original studies from inception, up to December 2021. Random-effects meta-analyses were conducted. Sixteen studies participated in the qualitative synthesis, of which k = 14 fetched quantitative data encompassing a total of 13,424,760 participants and 217,089 individuals with BD. Both fathers [adjusted for the age of other parent and socioeconomic status odd ratio - OR = 1.29(95%C.I. = 1.13-1.48)] and mothers aged ≤ 20 years [(OR = 1.23(95%C.I. = 1.14-1.33)] had consistently increased odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Fathers aged ≥ 45 years [adjusted OR = 1.29 (95%C.I. = 1.15-1.46)] and mothers aged 35-39 years [OR = 1.10(95%C.I. = 1.01-1.19)] and 40 years or older [OR = 1.2(95% C.I. = 1.02-1.40)] likewise had inflated odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Early and delayed parenthood are associated with an increased risk of BD in the offspring. Mechanisms underlying this association are largely unknown and may involve a complex interplay between psychosocial, genetic and biological factors, and with different impacts according to sex and age range. Evidence on the association between parental age and illness onset is still tentative but it points towards a possible specific effect of advanced paternal age on early BD-onset.

The present study is focused on the development and characterization of innovative cementitious-based composite sensors. In particular, multifunctional cement mortar composites with enhanced functional, piezo-resistive, properties are designed with Multiwall Carbon Nanotube-MWCNTs and reduced Graphene Oxide-rGO dispersed in a natural-rubber latex aqueous dispersion, by exploiting both the concept of confining of the conductive filler in the polymeric phase. The manufactured cement-based composites were characterized by means of Inelastic Neutron Scattering to assess the hydration reactions and the interactions of natural rubber with the hydrated cement phases and by Electron Scanning Microscopy and X-Ray diffraction to evaluate the morphological and mineralogical structure, respectively. Piezo-resistive properties to assess electro-mechanical behavior in strain condition are also measured. The results show that the presence of natural-rubber latex permits to obtain a three-dimensional rGO/MWCNTs segregate structure which catalyzes the formation of hydrated phases of the cement and increases the piezo-resistive sensitivity of mortar composites, representing a reliable approach in developing innovative mortar-based piezoresistive strain sensors.

This paper examines the loan loss provisioning behaviour during the transition from IAS 39 to IFRS 9 for a sample of 403 banks in 27 countries in European Union. The objective of the study is to investigate whether during the first years of adoption of the new expected credit loss (ECL) impairment model banks are more en-couraged to smooth earnings and manage capital, compared to the previous in-curred loss (ICL) model. Results show that under ECL, banks adopt a more ag-gressive opportunistic behaviour in accordance with the income-smoothing and capital management approach. Management should be aware of this to implement monitoring and control systems, increasing trustworthiness of financial in-formation for investors' expectations.

Drop-out from follow-up visits carries significant burden for people diagnosed with depression. The present study assesses multiple clinical moderators of drop-out among depressed outpatients. We retrospectively followed-up 131 outpatients over 6 months: 78 major depressive disorder (MDD), and 53 bipolar disorder (BD-I = 24; BD-II = 29) patients diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Participants were assessed with standard rating scales administered by experienced psychiatrists. Upon descriptive and Cox regression analyses, 17/53 BDs (32%) dropped-out; the overall survival time until drop-out was 57.94 ± 17.79 days. BD drop-outs were younger, had an earlier age at onset, shorter illness duration, lower rates of lifetime obsessive-compulsive disorder/suicidal behavior, higher rates of substance use disorder (SUD), anxious and mixed features of depression compared to BDs attending up to six months. Among MDD patients, 10/78 cases (13%) dropped-out by month-6 with an average survival of 42.40 ± 16.45 days. Earlier age of onset, younger age, positive family history for mood disorders, lower rates of lifetime generalized anxiety disorder were significantly more frequent among drop-outs than completers, as opposite to SUD, and lifetime recurrent depression. Older age predicted lower drop-out among BDs and MDDs, although with almost null hazard ratio (HR) = 0.928, p < 0.01 vs. HR = 0.941, p < 0.01, respectively. Higher rates of lifetime SUD predicted higher drop-out rates by month-6 among MDDs (HR = 5.477, p = 0.02). Limitations of the study: retrospective design, small sample size, lack of objective measures of treatment-adherence/mood rating during follow-up. Drop-out is common in the real-world setting, warranting specific interventions since the beginning of the treatment.

The increase in multidrug-resistant bacteria represents a true challenge in the pharmaceutical and biomedical fields. For this reason, research on the development of new potential antibacterial strategies is essential. Here, we describe the development of a green system for the synthesis of silver nanoparticles (AgNPs) bioconjugated with chitosan. We optimized a Prunus cerasus leaf extract as a source of silver and its conversion to chitosan–silver bioconjugates (CH-AgNPs). The AgNPs and CH-AgNPs were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FT-IR), ultraviolet–visible spectroscopy (UV–Vis), and zeta potential measurement (Z-potential). The cytotoxic activity of AgNPs and CH-AgNPs was assessed on Vero cells using the 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) cell proliferation assay. The antibacterial activity of AgNPs and CH-AgNPs synthesized using the green system was determined using the broth microdilution method. We evaluated the antimicrobial activity against standard ATCC and clinically isolated multisensitive (MS) and multidrug-resistant bacteria (MDR) Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Klebsiella pneumonia (K. pneumoniae), and Staphylococcus aureus (S. aureus), using minimum inhibitory concentration (MIC) assays and the broth dilution method. The results of the antibacterial studies demonstrate that the silver chitosan bioconjugates were able to inhibit the growth of MDR strains more effectively than silver nanoparticles alone, with reduced cellular toxicity. These nanoparticles were stable in solution and had wide-spectrum antibacterial activity. The synthesis of silver and silver chitosan bioconjugates from Prunus cerasus leaf extracts may therefore serve as a simple, ecofriendly, noncytotoxic, economical, reliable, and safe method to produce antimicrobial compounds with low cytotoxicity.

Although still needing a definite theoretical status, spatial justice represents an inspiring framework for geographical analysis and for planning. In this paper we try to operationalize the concept through a geo-demographic approach. By using demographic and social differences as proxy of the concept at the urban level we define five socio-territorial clusters based on the characteristics of the population residing in the enumeration area of 14 Italian local labour market areas (LLMAs) whose capital is also the capital of a metropolitan city. The first results of the analysis show a high level of heterogeneity and the absence of compact and segregated peripheries. At the same time the analysis highlights the need for further methodological investigations to attain a better representation of social justice in its spatial dimension.

Spermatogenesis is an extraordinarily complex process, regulated by several factors, which leads to the differentiation of spermatogonia into spermatozoa. Among vertebrates, several reports have been focused on the lizard Podarcis sicula, a seasonal breeder and a good model for the study of reproductive processes. The goal of this review is to resume all the available data about systemic and above all local control factors involved in the control of P. sicula testicular activity. During the seasonal reproductive cycle, the variation of the expression levels of these factors determines significant variations that induce the activation or blocking of spermatogenesis. The data supplied in this review, in addition to analyze the current literature regarding the main actors of Podarcis sicula spermatogenesis, will hopefully provide a basic model that can be used for further studies on the intratesticular interaction between molecular factors that control spermatogenesis.

The goal of this study was to evaluate P450 aromatase localization in the epididymis of two different vertebrates: the lizard Podarcis sicula, a seasonal breeder, and Rattus rattus, a continuous breeder. P450 aromatase is a key enzyme involved in the local control of spermatogenesis and steroidogenesis and we proved for the first time that this enzyme is represented in the epididymis of both P. sicula and R. rattus. In details, P450 aromatase was well represented in epithelial and myoid cells and in the connective tissue of P. sicula epididymis during the reproductive period; instead, during autumnal resumption this enzyme was absent in the connective tissue. During the non-reproductive period, P450 aromatase was localized only in myoid cells of P. sicula epididymis, whereas in R. rattus it was localized both in myoid cells and connective tissue. Our findings, the first on the epididymis aromatase localization in the vertebrates, suggest a possible role of P450 aromatase in the control of male genital tract function, particularly in sperm maturation.

The influence of the masonry infills on the seismic performances of Reinforced Concrete (RC) frames is generally evaluated in analytical and numerical studies by adopting the equivalent strut model; it is based on experimental observations showing that at the onset of damage, stresses migrate to the diagonal of the panel and are transferred to the surrounding frame through the contact zones at the corners. Above the different equivalent strut models available in literature, single-strut models are generally used to evaluate the global behaviour, while multi-strut approaches are preferred to investigate on local interaction phenomena between panel and frame. In case of existing buildings, with poor transversal reinforcement of the columns, the presence of the infills can lead to pre-emptive brittle failure. The present study is aimed at evaluating the influence of the modelling approach on the evaluation of the seismic performance both in terms of global and local behaviour. Nonlinear dynamic analyses have been performed on an 8-storey infilled RC frame, following the Incremental Dynamic Analysis procedure, in order to evaluate structural performances depending on the model adopted to simulate the infills.

As the most widely used construction material, concrete is constantly in development with continuous advances made in the fields of material science, concrete technology and reinforcement systems. The development of fiber reinforced concrete (FRC) has significantly impacted all three fields. Since the first trials with FRC in the 1960s, the material has undergone significant improvements in both the quality of the materials as well as the understanding of its structural behavior. Nevertheless, despite nearly 50 years of development, research on FRC has been focusing almost exclusively on its fresh state properties and on its short-term characteristics. Additionally, the composite material FRC has often been the sole subject of experimental campaigns, rather than the constituents and FRC together. Finally, the use of FRC is not yet widely incorporated in design codes, but typically, structural design approaches consider only the short-term strength and assume FRC to be a one-phased material. In this thesis, both simplifications are abandoned with the aim to investigate the creep behavior of cracked FRC in a multi-scale and two-phased approach. To that end, a combined methodology consisting of experimental work, numerical simulations and sectional analyses is adopted. Firstly, an extensive experimental campaign consisting of nearly 300 tests is completed on two types of polypropylene FRC. The short-term and creep properties are investigated at three different scales: fiber, fiber-matrix interface and the composite scale. The aim of the short-term tests is to characterize the material under various types of loading or with various test parameters. The creep tests investigate the long-term behavior at different load ratios, for time scales up to 9 months. The current study represents the first time such an extended time scale is considered in a multi-scale approach for the creep of FRC. The experiments highlight the importance of the fiber properties and the creep load ratio on the observed behavior across all scales. Secondly, a numerical model is developed to describe and predict the creep behavior of cracked FRC, based on the short-term and creep properties of its constituents (fiber and fiber-matrix interface). To that end, a two-phased finite element model is constructed where the fibers of a so-called fiber set are considered separately from the concrete matrix. Different fiber sets are generated and a Monte-Carlo analysis is performed to statistically assess the influence of the fiber distribution on the creep behavior. This is the first time such a two-phased numerical approach is adopted to determine and predict the creep behavior of cracked FRC. The simulated creep behavior after 15 years predicts no structural failure and the average fiber stresses amount to only 10 % of the tensile strength. The initial deformation and first-week creep is overestimated by the model. Thirdly, the structural behavior of a cracked FRC section under sustained flexural loading is analyzed and discussed. A three-stage approach is presented to consecutively describe monotonic, cyclic and time-dependent flexural loading. For the latter, the flexural creep deformations are based on uniaxial creep data from the Model Code and the numerical analyses. Therefore, a more physical basis is provided to determine flexural creep, rather than relying on a phenomenological description with spring-dashpot systems. The proposed calculation method predicts the stress and deformation profile over the height of the cracked section and in time. The predicted data is compared to and validated with experimental measurements. A good agreement is found in the location of the neutral axis, the deformation profile and established inverse analysis methods for monotonic bending. As such, the proposed model can be used to predict the flexural creep deformations and time-dependent CMOD growth based on uniaxial creep data. status: published

The manufacturing technology of reinforced concrete with the use of steel fibers to improve its mechanical properties is well-known and commonly used in civil engineering. Generally, steel fibers as discontinuous reinforcement of the concrete matrix are used to limit the cracking growth following the load application. Thus, the obtained concrete is characterized by an improvement of the typically brittle behavior of the ordinary matrix, mainly referring to toughness and post-cracking behavior. In this paper the results of a recent experimental campaign carried out at the University of Salento will be discussed. It was designed to study the optimization of concrete mixtures reinforced with recycled steel fibers from end of life tires (ELTs) to be used for the realization of precast panels. This experimental campaign is part of a wider research project aimed to validate the idea that the constituent elements of the ELTs, especially rubber and steel, can be effectively reused in concrete mixtures. Taking into account the high annual amount of ELTs generated around the world and their negative impact on the global environmental sustainability, the recovery of their constituent materials and their reuse as raw materials in different technologies, is certainly an excellent way for a sustainable development.