A 2D ferroelectric vortex pattern in twisted BaTiO3 freestanding layers.

The wealth of complex polar topologies1-10 recently found in nanoscale ferroelectrics results from a delicate balance between the intrinsic tendency of the materials to develop a homogeneous polarization and the electric and mechanical boundary conditions imposed on them. Ferroelectric-dielectric interfaces are model systems in which polarization curling originates from open circuit-like electric boundary conditions, to avoid the build-up of polarization charges through the formation of flux-closure11-14 domains that evolve into vortex-like structures at the nanoscale15-17 level. Although ferroelectricity is known to couple strongly with strain (both homogeneous18 and inhomogeneous19,20), the effect of mechanical constraints21 on thin-film nanoscale ferroelectrics has been comparatively less explored because of the relative paucity of strain patterns that can be implemented experimentally. Here we show that the stacking of freestanding ferroelectric perovskite layers with controlled twist angles provides an opportunity to tailor these topological nanostructures in a way determined by the lateral strain modulation associated with the twisting. Furthermore, we find that a peculiar pattern of polarization vortices and antivortices emerges from the flexoelectric coupling of polarization to strain gradients. This finding provides opportunities to create two-dimensional high-density vortex crystals that would enable us to explore previously unknown physical effects and functionalities.

Extremely long-range, high-temperature Josephson coupling across a half-metallic ferromagnet.

The Josephson effect results from the coupling of two superconductors across a spacer such as an insulator, a normal metal or a ferromagnet to yield a phase coherent quantum state. However, in junctions with ferromagnetic spacers, very long-range Josephson effects have remained elusive. Here we demonstrate extremely long-range (micrometric) high-temperature (tens of kelvins) Josephson coupling across the half-metallic manganite La0.7Sr0.3MnO3 combined with the superconducting cuprate YBa2Cu3O7. These planar junctions, in addition to large critical currents, display the hallmarks of Josephson physics, such as critical current oscillations driven by magnetic flux quantization and quantum phase locking effects under microwave excitation (Shapiro steps). The latter display an anomalous doubling of the Josephson frequency predicted by several theories. In addition to its fundamental interest, the marriage between high-temperature, dissipationless quantum coherent transport and full spin polarization brings opportunities for the practical realization of superconducting spintronics, and opens new perspectives for quantum computing.

Expression of mBD4, mBD3 and CRAMP during type II collagen-induced arthritis/CIA and their association with inflammation and bone-remodeling markers.

The aim of this study was to analyze the expression of mBD4, mBD3 and CRAMP in joint of mice with type II collagen-induced arthritis/CIA and to explore its possible association with IL-10, IL-4, IFN-γ, IL-17, MMP3, RANK/RANKL/OPG and histological parameters. METHODS: CIA was induced in 44 DBA/1 J mice. The joints from mice were classified into the onset, peak and remission phase of CIA. Histological sections were stained with hematoxylin-eosin and safranin O. The expression of CRAMP, mBD-3, mBD-4, and MMP-3 was evaluated using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The expression of IL-10, IL-4, IFN-γ, IL-17, RANK/RANKL/OPG was analyzed by RT-PCR. RESULTS: We observed that inflammation and immunostained cells for CRAMP increased in the peak and remission phases compared to the control group. In addition, increments in relative expressions of CRAMP were detected for the remission phase and in IL-4 and IL-17 in the peak phase compared to the control and onset phase. In addition, an increase in IL-10 in a peak phase compared to the control, as well as the relative expression of IFN-γ in remission phase was higher than in the onset phase. This was accompanied by an increase in cartilage damage in the peak phase compared to the control. Cells immunostained to MMP3 increased in the peak phase compared to the onset and control group, and relative expression of MMP3 was detected in the peak phase compared to the onset, remission, and control group. We observed that the relative expression of RANK and RANKL in the peak phase was higher than in control and onset phase. Finally, the relative expression of OPG in the peak phase compared to the onset, remission, and control group was detected. Regarding CRAMP behavior in the different phases studied, it was positively correlated with IL-4 and RANK, and showed a negative correlation with IFN-γ, IL-17, IL-10, RANKL, OPG and RANKL/OPG ratio in the control group. Also was positively correlated with IFN-γ, IL-17, IL-4, IL-10, as well as with RANK, RANKL, and OPG in the onset and peak phases of the CIA. In the peak phase, CRAMP showed a positive association with MMP3, and we observed a direct correlation between CRAMP and IFN-γ and RANKL/OPG ratio in remission phase. mBD3 correlates positively with IFN-γ, IL-17, IL-10, RANKL, OPG and RANKL/OPG ratio, and showed a negative correlation with CRAMP, MMP3, and RANK in the control group. Also, it was directly associated with IFN-γ, IL-17, IL-4, IL-10 and RANKL in the onset phase while it was inversely associated with CRAMP, MMP-3, RANK, RANKL, and OPG in the peak phase. Finally, mBD3 was inversely correlated with MMP3 in the remission phase and was directly associated with CRAMP, IFN-γ and RANKL/OPG ratio in this phase. mBD4 was directly associated with CRAMP, IFN-γ, IL-17, IL-4, IL-10, RANKL / OPG in the onset phase, and with CRAMP, IFN-γ, IL-17, IL-4, IL-10, MMP3, RANK, RANKL and OPG in the peak phase. Finally, mBD4 was positively associated with mBD3, IFN-γ, IL-17, IL-10, RANK, RANKL OPG and RANKL/OPG in the CIA remission phase. CONCLUSIONS: Our results demonstrate that CRAMP plays an important role in CIA progress and suggest that its abundance is associated with local pro- and anti-inflammatory status. This makes us propose CRAMP as a possible contributor of bone reconstruction in the last stage of CIA.

Controlled Sign Reversal of Electroresistance in Oxide Tunnel Junctions by Electrochemical-Ferroelectric Coupling.

The persistence of ferroelectricity in ultrathin layers relies critically on screening or compensation of polarization charges which otherwise destabilize the ferroelectric state. At surfaces, charged defects play a crucial role in the screening mechanism triggering novel mixed electrochemical-ferroelectric states. At interfaces, however, the coupling between ferroelectric and electrochemical states has remained unexplored. Here, we make use of the dynamic formation of the oxygen vacancy profile in the nanometer-thick barrier of a ferroelectric tunnel junction to demonstrate the interplay between electrochemical and ferroelectric degrees of freedom at an oxide interface. We fabricate ferroelectric tunnel junctions with a La_{0.7}Sr_{0.3}MnO_{3} bottom electrode and BaTiO_{3} ferroelectric barrier. We use poling strategies to promote the generation and transport of oxygen vacancies at the metallic top electrode. Generated oxygen vacancies control the stability of the ferroelectric polarization and modify its coercive fields. The ferroelectric polarization, in turn, controls the ionization of oxygen vacancies well above the limits of thermodynamic equilibrium, triggering the build up of a Schottky barrier at the interface which can be turned on and off with ferroelectric switching. This interplay between electronic and electrochemical degrees of freedom yields very large values of the electroresistance (more than 10^{6}% at low temperatures) and enables a controlled switching between clockwise and counterclockwise switching modes in the same junction (and consequently, a change of the sign of the electroresistance). The strong coupling found between electrochemical and electronic degrees of freedom sheds light on the growing debate between resistive and ferroelectric switching in ferroelectric tunnel junctions, and moreover, can be the source of novel concepts in memory devices and neuromorphic computing.

Oxygen intercalation in PVD graphene grown on copper substrates: A decoupling approach.

We investigate the intercalation process of oxygen in-between a PVD-grown graphene layer and different copper substrates as a methodology for reducing the substrate-layer interaction. This growth method leads to an extended defect-free graphene layer that strongly couples with the substrate. We have found, by means of X-ray photoelectron spectroscopy, that after oxygen exposure at different temperatures, ranging from 280 °C to 550 °C, oxygen intercalates at the interface of graphene grown on Cu foil at an optimal temperature of 500 °C. The low energy electron diffraction technique confirms the adsorption of an atomic oxygen adlayer on top of the Cu surface and below graphene after oxygen exposure at elevated temperature, but no oxidation of the substrate is induced. The emergence of the 2D Raman peak, quenched by the large interaction with the substrate, reveals that the intercalation process induces a structural undoing. As suggested by atomic force microscopy, the oxygen intercalation does not change significantly the surface morphology. Moreover, theoretical simulations provide further insights into the electronic and structural undoing process. This protocol opens the door to an efficient methodology to weaken the graphene-substrate interaction for a more efficient transfer to arbitrary surfaces.

Ferroelectric Control of Interface Spin Filtering in Multiferroic Tunnel Junctions.

The electronic reconstruction occurring at oxide interfaces may be the source of interesting device concepts for future oxide electronics. Among oxide devices, multiferroic tunnel junctions are being actively investigated as they offer the possibility to modulate the junction current by independently controlling the switching of the magnetization of the electrodes and of the ferroelectric polarization of the barrier. In this Letter, we show that the spin reconstruction at the interfaces of a La_{0.7}Sr_{0.3}MnO_{3}/BaTiO_{3}/La_{0.7}Sr_{0.3}MnO_{3} multiferroic tunnel junction is the origin of a spin filtering functionality that can be turned on and off by reversing the ferroelectric polarization. The ferroelectrically controlled interface spin filter enables a giant electrical modulation of the tunneling magnetoresistance between values of 10% and 1000%, which could inspire device concepts in oxides-based low dissipation spintronics.

Tuning the size, composition and structure of Au and Co50Au50 nanoparticles by high-power impulse magnetron sputtering in gas-phase synthesis.

Gas-phase synthesis of nanoparticles with different structural and chemical distribution is reported using a circular magnetron sputtering in an ion cluster source by applying high-power impulses. The influence of the pulse characteristics on the final deposit was evaluated on Au nanoparticles. The results have been compared with the more common direct current approach. In addition, it is shown for the first time that high-power impulses in magnetron based gas aggregation sources allows the growth of binary nanoparticles, CoAu in this case, with a variety of crystalline and chemical arrangements which are analyzed at the atomic level.

High-quality PVD graphene growth by fullerene decomposition on Cu foils.

We present a new protocol to grow large-area, high-quality single-layer graphene on Cu foils at relatively low temperatures. We use C60 molecules evaporated in ultra high vacuum conditions as carbon source. This clean environment results in a strong reduction of oxygen-containing groups as depicted by X-ray photoelectron spectroscopy (XPS). Unzipping of C60 is thermally promoted by annealing the substrate at 800ºC during evaporation. The graphene layer extends over areas larger than the Cu crystallite size, although it is changing its orientation with respect to the surface in the wrinkles and grain boundaries, producing a modulated ring in the low energy electron diffraction (LEED) pattern. This protocol is a self-limiting process leading exclusively to one single graphene layer. Raman spectroscopy confirms the high quality of the grown graphene. This layer exhibits an unperturbed Dirac-cone with a clear n-doping of 0.77 eV, which is caused by the interaction between graphene and substrate. Density functional theory (DFT) calculations show that this interaction can be induced by a coupling between graphene and substrate at specific points of the structure leading to a local sp3 configuration, which also contribute to the D-band in the Raman spectra.

Beard alopecia areata: a multicentre review of 55 patients.

BACKGROUND: Alopecia areata on the beard area (BAA) is a common clinical manifestation, but there are no studies about its characteristics. OBJECTIVE: To describe the epidemiology, comorbidities, clinical presentation, evolution, diagnostic findings and therapeutic choices in a series of patients with BAA. METHODS: This retrospective multicentre review included patients diagnosed with BAA as the first and unique clinical manifestation with at least 12 months of follow-up. Diagnosis was performed based on the typical clinical features. Extra-beard involvement was monitored in all cases. RESULTS: Overall, 55 male patients with a mean age of 39.1 years (range 20-74) were included. Twenty-five patients (45.5%) developed alopecia of the scalp during follow-up and more than 80% of cases appeared in the first 12.4 months. Clinical presentation of AA on the scalp was patchy AA (less than 5 patches) (52%), multifocal AA (28%), AA totalis (12%) and AA universalis (8%). Multivariate analysis revealed a trend of association between scalp involvement and family history of AA without statistical significance. CONCLUSIONS: According to this study, BAA may progress to scalp AA in a significant number of patients (45.5% of the patients with a follow-up interval of at least 12 months). In the group of patients who developed scalp AA, 80% of them did it within the first 12 months, so follow-up of patients with BAA is highly encouraged.

Alopecia areata totalis and universalis: a multicenter review of 132 patients in Spain.

BACKGROUND: Alopecia areata totalis (AAT) and universalis (AAU) pose a therapeutic challenge. OBJECTIVE: To describe the clinical and epidemiological features, therapeutic response and prognostic factors in a large series of patients diagnosed with AAT and AAU. METHODS: This retrospective multicenter study included patients diagnosed with AAT/AAU with a minimum follow-up of 12 months. Response was assessed based on the regrowth of scalp hair. RESULTS: In all, 132 patients (92 women and 40 men) - 80 (61%) diagnosed with AAU and 52 (39%) diagnosed with AAT - were included. The median time between the presentation of alopecia areata (AA) and the development of extensive AA was 1 year and it was less than 4 years in 121 patients (91%). There was an initial response to treatment in 64% of patients, although only 14% presented a persistent response. Adverse side effects from the medications used were detected in 33% of patients. The prognostic factors associated with poor response were the presence of AAU and a positive family history of AA. CONCLUSIONS: Treatment of AAT and AAU is challenging. Although an initial regrowth may be achieved, the duration of response is usually short. There were no significant differences on the effectiveness or duration of response between the various systemic therapies.

Formation of biomineral iron oxides compounds in a Fe hyperaccumulator plant: Imperata cylindrica (L.) P. Beauv.

We report a detailed work of composition and location of naturally formed iron biominerals in plant cells tissues grown in iron rich environments as Imperata cylindrica. This perennial grass grows on the Tinto River banks (Iberian Pyritic Belt) in an extreme acidic ecosystem (pH∼2.3) with high concentration of dissolved iron, sulphate and heavy metals. Iron biominerals were found at the cellular level in tissues of root, stem and leaf both in collected and laboratory-cultivated plants. Iron accumulated in this plant as a mix of iron compounds (mainly as jarosite, ferrihydrite, hematite and spinel phases) was characterized by X-ray diffraction (XRD), X-ray absorption spectroscopy (XAS), Mössbauer spectroscopy (MS), magnetometry (SQUID), electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX; TEM-EDX; HRSTEM). A low fraction of phosphorous was detected in this iron hyperaccumulator plant. Root and rhizomes tissues present a high proportion of ferromagnetic iron oxide compounds. Iron oxides-rich zones are localized in electron dense intra and inter-cellular aggregates that appear as dark deposits covering the inner membrane and organelles of the cell. This study aims to contribute to a better understanding of the mechanisms of accumulation, transport, distribution of iron in Imperata cylindrica.

Proximity Driven Commensurate Pinning in YBa2Cu3O7 through All-Oxide Magnetic Nanostructures.

The design of artificial vortex pinning landscapes is a major goal toward large scale applications of cuprate superconductors. Although disordered nanometric inclusions have shown to modify their vortex phase diagram and to produce enhancements of the critical current ( MacManus-Driscoll , J. L. ; Foltyn , S. R. ; Jia , Q. X. ; Wang , H. ; Serquis , A. ; Civale , L. ; Maiorov , B. ; Hawley , M. E. ; Maley , M. P. ; Peterson , D. E. Nat. Mater. 2004 , 3 , 439 - 443 and Yamada , Y. ; Takahashi , K. ; Kobayashi , H. ; Konishi , M. ; Watanabe , T. ; Ibi , A. ; Muroga , T. ; Miyata , S. ; Kato , T. ; Hirayama , T. ; Shiohara , Y. Appl. Phys. Lett. 2005 , 87 , 1 - 3 ), the effect of ordered oxide nanostructures remains essentially unexplored. This is due to the very small nanostructure size imposed by the short coherence length, and to the technological difficulties in the nanofabrication process. Yet, the novel phenomena occurring at oxide interfaces open a wide spectrum of technological opportunities to interplay with the superconductivity in cuprates. Here, we show that the unusual long-range suppression of the superconductivity occurring at the interface between manganites and cuprates affects vortex nucleation and provides a novel vortex pinning mechanism. In particular, we show evidence of commensurate pinning in YBCO films with ordered arrays of LCMO ferromagnetic nanodots. Vortex pinning results from the proximity induced reduction of the condensation energy at the vicinity of the magnetic nanodots, and yields an enhanced friction between the nanodot array and the moving vortex lattice in the liquid phase. This result shows that all-oxide ordered nanostructures constitute a powerful, new route for the artificial manipulation of vortex matter in cuprates.

Regulatory T-cell subsets in response to specific Mycobacterium tuberculosis antigens in vitro distinguish among individuals with different QTF and TST reactivity.

Regulatory T cells (Tregs), a subset of CD4+ T cells related with immune regulation, have been associated with active and latent tuberculosis infection (LTBI). Treg frequencies were evaluated by multicolor flow cytometry (FC) in peripheral blood mononuclear cells (PBMCs) stimulated with mycobacterial antigens ESAT-6, CFP-10, and TB7.7 to assess their capacity to distinguish subjects with different reactivity to the QuantiFERON-TB® Gold In-Tube (QFT-IT) test and the tuberculin skin test (TST). Increased frequencies of CD4+CD25highCD39+ cells were found for the [TST+, QTF+] compared with the [TST+, QTF-] group. Also, higher frequencies were observed for the [TST+, QTF+] compared with the [TST+, QTF-] and [TST-, QTF-] groups in CD4+CD25highFoxp3+ and CD4+CD25highCD39+Foxp3+ populations. Receiver operating characteristics (ROC curve) analysis confirmed these discriminating results. QFT-IT and TST quantitative values correlated with several Treg population frequencies.

Analysis of Th1, Th17 and regulatory T cells in tuberculosis case contacts.

We have hypothesized that individuals infected with Mycobacteriumtuberculosis that exhibit different patterns of immune reactivity in serial interferon (IFN)-γ release assays (IGRA's) correspond to different status within the immune spectrum of latent tuberculosis (TB). Accordingly, we analyzed the possible association between the consistent results (negative or positive) in an IGRA test and relevant immune parameters, mainly the levels of Th1 and Th17 lymphocytes and T regulatory (Treg) cells in the peripheral blood of TB case contacts. We found that individuals with a persistently positive IGRA showed increased levels of Th1 and Th17 lymphocytes upon in vitro stimulation with MTB antigens. In addition, a significant increase in the proportion of CD4+CTLA-4+ and CD4+Foxp3+ cells was detected in assays with blood samples from these individuals. Our data support that different immune phenotypes can be identified into the spectrum of latent TB, by combining different parameters of immune reactivity against MTB.

Pattern-wavelength coarsening from topological dynamics in silicon nanofoams.

We report the experimental observation of a submicron cellular structure on the surface of silicon targets eroded by an ion plasma. Analysis by atomic force microscopy allows us to assess the time evolution and show that the system can be described quantitatively by the convective Cahn-Hilliard equation, found in the study of domain coarsening for a large class of driven systems. The space-filling trait of the ensuing pattern relates it to evolving foams. Through this connection, we are actually able to derive the coarsening law for the pattern wavelength from the nontrivial topological dynamics of the cellular structure. Thus, the study of the topological properties of patterns in nonvariational spatially extended systems emerges as complementary to morphological approaches to their challenging coarsening properties.

[SYSTEMATIZATION, ORDER AND SECURITY AS A RESULT OF THE NURSE ASSESSMENT IN PAEDIATRIC EMERGENCY: A METAMORPHOSIS PROCESS]. / Sistemática, orden y seguridad como resultado de la valoración enfermera en la urgencia pediátrica un proceso de metamorfosis.

OBJECTIVE: To determine from the health care professionals perspective the impact on clinical practice of incorporating an assessment tool for primary care paediatric emergency. METHOD: Qualitative study based on the collection of written documents. Twenty-four wide and detailed documents were collected. Thematic analysis was used. RESULTS: Participants were 9 nurses and 7 paediatricians, all with experience in the Paediatric Emergency Department. The results are grouped into three areas: perception of previous situation; benefits perceived; difficulties of the change process related to the triage instrument. The benefits perceived include the achievement of the objectives related to triage as well as collateral benefits for the organization and distribution of structural resources, adequacy of human resources, self-assessment and professional recognition, improvement of team communication and users service perception. The difficulties identified are related to the feasibility of using this instrument when patient flow is high and to the need of specialized training. CONCLUSIONS: All participants perceived more benefits than disadvantages, and both nurses and paediatricians experienced the process as a positive experience. The introduction of the assessment tool had a broader impact than expected.

Matrix and interaction effects on the magnetic properties of Co nanoparticles embedded in gold and vanadium.

The study of the magnetic properties of Co nanoparticles (with an average diameter of 10.3 nm) grown using a gas-phase aggregation source and embedded in Au and V matrices is presented. We investigate how the matrix, the number of embedded nanoparticles (counted by coverage percentage), the interparticle interactions and the complex nanoparticles/matrix interface structure define the magnetic properties of the studied systems. A threshold coverage of 3.5% of a monolayer was found in both studied systems: below this coverage, nanoparticles behave as an assembly of independent single-domain magnetic entities with uniaxial anisotropy. Above the threshold it is found that the magnetic behavior of the systems is more matrix dependent. While magnetic relaxation and Henkel plots measurements stress the importance of the dipolar interactions and the formation of coherent clusters in the case of the Au matrix, the magnetic behavior of cobalt clusters embedded in the vanadium matrix is explained through the formation of a spin glass-like state at the V-Co interface that screens the magnetic interactions between NPs.

Study of frontal hairline patterns in Spanish Caucasian women.

BACKGROUND: Anterior hairline measurements and their possible relationship with androgen levels, sebum production, and skin hydration have not been reported in white Spanish women. MATERIAL AND METHODS: This was a prospective descriptive and analytical observational study conducted on 103 healthy premenopausal white Spanish women recruited from the health staff of Hospital Universitario Virgen Macarena in Seville, Spain. Measurements were made of anterior hairline implantation, sebum levels, and the degree of hydration of the stratum corneum. Androgen levels were also determined in 50 volunteers from this group 3 to 5 days after the end of the menstrual cycle. RESULTS: The mean age of the women was 29.7 years. A widow's peak was observed in 94.17% of the group. The mean dimensions of the widow's peak were a height of 1.01 cm and width of 2.13 cm. The mean hormone levels were within normal limits for our hospital's laboratory with the exception of 17-hydroxyprogesterone, with a mean level of 1.39 ng/mL (range, 0.6-5.9ng/mL; normal limits, 0.15-1.10 ng/mL). The mean prostate specific antigen level was 0.04ng/mL (range 0.02-0.08ng/mL; normal limits, 0.00-0.02ng/mL). CONCLUSIONS: The hairline measurements of the white Spanish women in this study differ from those reported in American women. Knowledge of this normal pattern of anterior hairline implantation can be important in the evaluation of women with female androgenetic alopecia with male pattern, frontal fibrosing alopecia, or other established scarring alopecia seeking a surgical solution by hair transplantation.

Sodium Selenite Diminished the Regulatory T Cell Differentiation In Vitro.

Sodium selenite modulates the activity of lymphocytes. It negatively regulates the suppressive activity of cells and increases the immune response. In this study, we evaluated whether the regulatory T cell differentiation was modulated by sodium selenite. The percentages of CD4+CD25+Foxp3+, CD4+CD25+, and CD4+CTLA-4+ cells in CD4+ T cells cultures stimulated with IL-2 and TGF-ß in the presence or absence of selenium, in the form of sodium selenite (2.0×10-6M), were evaluated by flow cytometry. The mRNA expression of TET2/3 enzymes and IL-10 was analyzed by RT-qPCR and the levels of IL-10 were measured by an ELISA. We observed a decrease in CD4+CD25+Foxp3+ and CD4+CTLA-4+ cells in presence of selenium. However, normal percentages were reached again after selenium removal. An increase in CD4+CTL4-4+ cells was detected in selenium-primed cell cultures in absence of IL-2 and TGF-ß. In addition, we observed a decrease in TET3 in presence of selenium. Finally, we observed an augment in IL-10 transcription and protein levels and relative expression of TET2 in cultures exposed to selenium. We suggest that selenium reversibly affects the regulatory T cell differentiation in vitro. Likewise, selenium may modulate Treg percentages promoting optimal immune responses and, at the same time, the expression of specific suppressor molecules.

Dynamic of total internal reflection (2+1)D bright beams on photorefractive SBN61:Ce crystal.

We study experimentally and numerically the transient behavior of a (2+1)D beam when it is totally reflected by nonlinear interface formed by SBN61:Ce photorefractive crystal. The dynamics give rise to observation of new beams. Due to modulation instability of the beam, the nonlinear interface stimulates the break of the beam into new beams that are reflected to different angles.