Neural oscillations underlying the neural gating of respiratory sensations in generalized anxiety disorder.

Individuals with generalized anxiety disorder (GAD) have been shown to have altered neural gating of respiratory sensations (NGRS) using respiratory-related evoked potentials (RREP); however, corresponding neural oscillatory activities remain unexplored. The present study aimed to investigate altered NGRS in individuals with GAD using both time and time-frequency analysis. Nineteen individuals with GAD and 28 healthy controls were recruited. Paired inspiratory occlusions were delivered to elicit cortical neural activations measured from electroencephalography. The GAD group showed smaller N1 amplitudes to the first stimulus (S1), lower evoked gamma and larger evoked beta oscillations compared to controls. Both groups showed larger N1, P3, beta power and theta power in response to S1 compared to S2, suggesting a neural gating phenomenon. These findings suggest that N1, gamma and beta frequency oscillations may be indicators for altered respiratory sensation in GAD populations and that the N1, P3, beta and theta oscillations can reflect the neural gating of respiratory sensations.

First Direct Observation of Collider Neutrinos with FASER at the LHC.

We report the first direct observation of neutrino interactions at a particle collider experiment. Neutrino candidate events are identified in a 13.6 TeV center-of-mass energy pp collision dataset of 35.4 fb^{-1} using the active electronic components of the FASER detector at the Large Hadron Collider. The candidates are required to have a track propagating through the entire length of the FASER detector and be consistent with a muon neutrino charged-current interaction. We infer 153_{-13}^{+12} neutrino interactions with a significance of 16 standard deviations above the background-only hypothesis. These events are consistent with the characteristics expected from neutrino interactions in terms of secondary particle production and spatial distribution, and they imply the observation of both neutrinos and anti-neutrinos with an incident neutrino energy of significantly above 200 GeV.

Surface Modification of Li3VO4 with PEDOT:PSS Conductive Polymer as an Anode Material for Li-Ion Capacitors.

Li3VO4 (LVO) is a highly promising anode material for lithium-ion batteries, owing to its high capacity and stable discharge plateau. However, LVO faces a significant challenge due to its poor rate capability, which is mainly attributed to its low electronic conductivity. To enhance the kinetics of lithium ion insertion and extraction in LVO anode materials, a conductive polymer called poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is applied to coat the surface of LVO. This uniform coating of PEDOT:PSS improves the electronic conductivity of LVO, thereby enhancing the corresponding electrochemical properties of the resulting PEDOT:PSS-decorated LVO (P-LVO) half-cell. The charge/discharge curves between 0.2 and 3.0 V (vs. Li+/Li) indicate that the P-LVO electrode displays a capacity of 191.9 mAh/g at 8 C, while the LVO only delivers a capacity of 111.3 mAh/g at the same current density. To evaluate the practical application of P-LVO, lithium-ion capacitors (LICs) are constructed with P-LVO composite as the negative electrode and active carbon (AC) as the positive electrode. The P-LVO//AC LIC demonstrates an energy density of 107.0 Wh/kg at a power density of 125 W/kg, along with superior cycling stability and 97.4% retention after 2000 cycles. These results highlight the great potential of P-LVO for energy storage applications.

Graph Neural Networks for Charged Particle Tracking on FPGAs.

The determination of charged particle trajectories in collisions at the CERN Large Hadron Collider (LHC) is an important but challenging problem, especially in the high interaction density conditions expected during the future high-luminosity phase of the LHC (HL-LHC). Graph neural networks (GNNs) are a type of geometric deep learning algorithm that has successfully been applied to this task by embedding tracker data as a graph-nodes represent hits, while edges represent possible track segments-and classifying the edges as true or fake track segments. However, their study in hardware- or software-based trigger applications has been limited due to their large computational cost. In this paper, we introduce an automated translation workflow, integrated into a broader tool called hls4ml, for converting GNNs into firmware for field-programmable gate arrays (FPGAs). We use this translation tool to implement GNNs for charged particle tracking, trained using the TrackML challenge dataset, on FPGAs with designs targeting different graph sizes, task complexites, and latency/throughput requirements. This work could enable the inclusion of charged particle tracking GNNs at the trigger level for HL-LHC experiments.

Preparation of Ni(OH)2/CuO heterostructures for improved photocatalytic degradation of organic pollutants and microorganism.

In this study, the Ni(OH)2/CuO heterostructured photocatalysts have been prepared via microwave (MW) hydrothermal method. The results indicate that the Ni(OH)2/CuO heterostructured composite exhibits a strong absorption in the UV and Vis regions. The construction of the heterojunction also improves the photogenerated carrier transport and inhibits the electron-hole separation due to the enhanced absorbance and the well alignment of the energy band at the Ni(OH)2/CuO interface. The photocatalytic capability of the heterostructured composites with different Ni(OH)2/CuO molar ratios is evaluated by the photodegradation of methylene blue under visible light illumination. The results reveal that the Ni(OH)2/CuO (1:1) heterostructures show the best photocatalytic efficiency, which is 2.18 and 6.13 times higher than that of pure Ni(OH)2 and CuO, respectively. Besides, the Ni(OH)2/CuO composites also reveal remarkable biocompatibility and strong photocatalytic activity in the degradation of antibiotics such as ciprofloxacin (CIP) and tetracycline (TC) and inactivation of Escherichia coli (E. coli).

Bio-Phenolic Resin Derived Porous Carbon Materials for High-Performance Lithium-Ion Capacitor.

In this article, hierarchical porous carbon (HPC) with high surface area of 1604.9 m2/g is prepared by the pyrolysis of rubberwood sawdust using CaCO3 as a hard template. The bio-oil pyrolyzed from the rubber sawdust, followed by the polymerization reaction to form resole phenolic resin, can be used as a carbon source to prepare HPC. The biomass-derived HPC shows a three-dimensionally interconnected morphology which can offer a continuous pathway for ionic transport. The symmetrical supercapacitors based on the as-prepared HPC were tested in 1.0 M tetraethylammonium tetrafluoroborate/propylene carbonate electrolyte. The results of electrochemical analysis show that the HPC-based supercapacitor exhibits a high specific capacitance of 113.3 F/g at 0.5 A/g with superior rate capability and cycling stability up to 5000 cycles. Hybrid lithium-ion capacitors (LICs) based on the HPC and Li4Ti5O12 (LTO) were also fabricated. The LICs have a maximum energy density of 113.3 Wh/kg at a power density of 281 W/kg. Moreover, the LIC also displays a remarkable cycling performance with a retention of 92.8% after 3000 cycles at a large current density of 0.75 A/g, suggesting great potential application in the energy storage of the LIC.

Fabrication of Ropivacaine/Dexamethasone-Eluting Poly(D, L-lactide-co-glycolide) Microparticles via Electrospraying Technique for Postoperational Pain Control.

Microencapsulation plays an important role in biomedical technology owing to its particular and attractive characteristics. In this work, we developed ropivacaine and dexamethasone loaded poly(D, L-lactide-co-glycolide) (PLGA) microparticles via electrospraying technique and investigated the release behavior of electrosprayed microparticles. The particle morphology of sprayed particles was assessed using scanning electron microscopy (SEM). The in vitro drug release kinetics were evaluated employing an elution method, and the in vivo pharmaceutical release as well as its efficacy on pain relief were tested using an animal activity model. The microscopic observation suggested that sprayed microparticles exhibit a size distribution of 5-6 µm. Fourier-transform infrared spectrometry and differential scanning calorimetry demonstrated the successful incorporation of pharmaceuticals in the PLGA particulates. The drugs-loaded particles discharged sustainably high concentrations of ropivacaine and dexamethasone at the target region in vivo for over two weeks, and the drug levels in the blood remained low. By adopting the electrospraying technique, we were able to prepare drug-embedded polymeric microparticles with effectiveness and with a sustainable capability for postoperative pain control.

Cancellation but not restraint ability is modulated by trait anxiety: An event-related potential and oscillation study using Go-Nogo and stop-signal tasks.

BACKGROUND: Trait anxiety has a detrimental effect on attention, which further leads to dysfunction of inhibitory control. However, there is no study examining how trait anxiety modulates inhibitory abilities on restraint and cancellation in the same subjects. Therefore, we aimed to use electrophysiological recordings to interrogate whether and to what extent trait anxiety modulated these two kinds of inhibitory functions. The Cognitive Failures Questionnaire (CFQ), a self-reported assessment of daily absentmindedness, was also used to examine its association with inhibition-related electrophysiological indicators. METHODS: Forty subjects were recruited from the top 10% (Higher Trait Anxiety [HTA], n= 20) and last 10% (Lower Trait Anxiety [LTA], n= 20) of the trait anxiety score distribution from 400 college students. During electrophysiological recordings, the Go-Nogo and stop-signal tasks were performed, which evaluated the abilities of restraint and cancellation, respectively. RESULTS: The HTA and LTA groups showed a comparable behavioral performance of restraint and cancellation abilities. However, the results of time-frequency analysis revealed that those with HTA demonstrated a stronger power of alpha oscillations (600‒1000 ms) in response to Stop trials in the stop-signal task, compared with individuals with LTA. Such oscillatory activity was positively correlated with the CFQ score. There was no significant between-group difference of the brain activation in the Go-Nogo task. LIMITATIONS: Future studies can recruit both individuals with trait anxiety and anxiety disorders to clarify the boundaries between healthy and pathological worries in terms of cancellation ability. CONCLUSIONS: cancellation, but not restraint, is modulated by trait anxiety.

Comparing the associations of three psychometric scales at baseline with long-term prognosis of depression over a 10-year period.

OBJECTIVE: The Depression and Somatic Symptoms Scale (DSSS), a free scale, includes depression (DS) and somatic (SS) subscales. This study aimed to compare the associations of the baseline DSSS, Hamilton Depression Rating Scale (HAMD) and Hospital Anxiety and Depression Scale (HADS) scores with the outcome of depression over a 10-year follow-up period. METHODS: Two hundred ninety outpatients with major depressive disorder (MDD) were enrolled and were followed-up at the 6-month, 2-year, and 10-year points. The three scales were administered at each follow-up. Multiple linear regressions were used to compare the associations. RESULTS: In a comparison of the HAMD, DS, and HADS-depression, the HAMD and DS scores at baseline were most strongly associated with the HAMD score at two (6-month and 2-year) and one (10-year) follow-up points, respectively. In a comparison of the HAMD, DS, SS, HADS-depression, and HADS-anxiety, the SS and HAMD scores at baseline were most strongly associated with the HAMD score at two (6-month and 10-year) and one (2-year) follow-up points, respectively. CONCLUSIONS: The DS, SS, and HAMD scores at baseline were significantly associated with the long-term outcome of depression. Scales or subscales assessing somatic symptoms might be more strongly associated with the outcome of depression.

Polyimide-Derived Carbon-Coated Li4Ti5O12 as High-Rate Anode Materials for Lithium Ion Batteries.

Carbon-coated Li4Ti5O12 (LTO) has been prepared using polyimide (PI) as a carbon source via the thermal imidization of polyamic acid (PAA) followed by a carbonization process. In this study, the PI with different structures based on pyromellitic dianhydride (PMDA), 4,4'-oxydianiline (ODA), and p-phenylenediamine (p-PDA) moieties have been synthesized. The effect of the PI structure on the electrochemical performance of the carbon-coated LTO has been investigated. The results indicate that the molecular arrangement of PI can be improved when the rigid p-PDA units are introduced into the PI backbone. The carbons derived from the p-PDA-based PI show a more regular graphite structure with fewer defects and higher conductivity. As a result, the carbon-coated LTO exhibits a better rate performance with a discharge capacity of 137.5 mAh/g at 20 C, which is almost 1.5 times larger than that of bare LTO (94.4 mAh/g).

The Association of Social Support and Symptomatic Remission among Community-Dwelling Schizophrenia Patients: A Cross-Sectional Study.

Schizophrenia is a mental disease that often leads to chronicity. Social support could reduce the severity of psychotic symptoms; therefore, its influence on remission should be examined. This study investigated the remission rates in community-dwelling schizophrenia patients and examined the association between social support and remission status. A cross-sectional study was conducted in 129 schizophrenia patients in Taiwan. Remission rates were evaluated, and the level of social support, clinical characteristics, sociodemographic variables, and healthy lifestyle status were compared between the remission and nonremission groups. The association between social support and remission was analyzed after adjusting for confounding factors. The mean illness duration is 12.9 years. More than 95% of the participants lived with their families, 63% were unemployed, and 43% achieved remission. Higher social support was observed in the remission group, and a significant correlation was observed between family domain of social support and remission status. Family support was a protective factor of symptomatic remission in community-dwelling schizophrenia patients in Taiwan. The results reflect the effects of a family-centered culture on patients during illness. Consequently, reinforcing family relationships and the capacity of families to manage the symptoms of patients and providing support to families are recommended.

Rapid Detection of Glucose on Nanostructured Gold Film Biosensor by Surface-Enhanced Raman Spectroscopy.

In this report, we summarized our development of biosensors for Rhodamine 6G and in vitro glucose detection based on surface-enhanced Raman scattering technology. For the detection of both Rhodamine 6G and in vitro glucose, a nature-patterned substrate with gold films over nanostructures (NPS-AuFON) was used as the surface-enhanced Raman scattering sensor platform. The enhancement factor was calculated at 9 × 107. In the processing of the substrate, cyclic voltammetry was used to form nano-gold particles under different conditions. The Rhodamine 6G and glucose detection were then achieved on this substrate. Furthermore, we combined the potentiostatic technique and electrochemical adsorption to best detect glucose in low concentrations. The glucose oxidation potential (100 mV) was used to capture glucose close to the surface of the NPS-AuFON. The quantitative detection of glucose in solution and in situ inspection were confirmed. Further, we determined that this surface modification technology can reach the goal of experiments set by the World Health Organization to judge whether or not a patient is a diabetic by detecting a glucose concentration of 11.1 mmol/L (mg/dL) at a minimum.

Reduced coupling of somatosensory gating and gamma oscillation in panic disorder.

Previous studies have reported that patients with panic disorder (PD) exhibited an aberrant level of GABA concentration, an inhibitory neurotransmitter in the human brain. However, it remains substantially unclear whether the inhibitory function regarding the neurophysiological characteristics is altered in this disease. Sensory gating (SG) is considered as an automatic inhibitory function in the sensory cortex. In addition, brain's gamma oscillation within the sensory cortex is another index to reflect inhibitory function. Here we aimed to investigate whether the patients with PD showed altered inhibitory function in the somatosensory system, including the primary (SI) and secondary (SII) somatosensory cortices. A total of 20 healthy controls and 21 patients with PD underwent magnetoencephalographic recordings. Paired-pulse and single-pulse paradigms were used to study SG and gamma oscillations, respectively. There were no significant between-group differences in the SG function in the SI and SII. However, patients with PD demonstrated a reduced gamma power in the SI. Among the healthy individuals, strong associations between SG ratios and gamma frequency values were observed in the SI. However, such a functional relationship disappeared among the patients with PD. We suggested the reduced coupling of SG and gamma oscillation as one of the neural signatures in PD.

Dysfunctional frontal activation of mismatch negativity in panic disorder: A magnetoencephalographic study.

BACKGROUND: Mismatch negativity (MMN) or its magnetic counterpart (MMNm) is a neurophysiological signal to reflect the automatic change-detection ability. However, MMN studies in patients with panic disorder (PD) showed contrasting results using electroencephalographic (EEG) recordings. The present study attempted to overcome the limitations of EEG methodology by means of a whole-head magnetoencephalography (MEG) combined with the depth-weighted minimum norm estimate method to conduct an in-depth investigation on the MMNm at the cortical level in patients with PD. METHODS: We recruited 22 healthy controls (HC) and 20 patients with PD to perform auditory oddball paradigm during MEG recordings. The cortical MMNm amplitudes and latencies in the superior temporal gyrus, inferior parietal lobule, and inferior frontal gyrus (IFG) were compared between the HC and PD groups. The correlations between MMNm responses and clinical measurement were also examined. RESULTS: Compared with the HC group, the PD group demonstrated significantly reduced MMNm amplitudes in the IFG. Furthermore, higher trait scores of the State-Trait Anxiety Inventory were associated with lower MMNm amplitudes of the right IFG among patients with PD. LIMITATIONS: Generalization of the current results to other settings or samples should be made cautiously due to the use of different medication regimens and presence of comorbidities in our patients. CONCLUSIONS: Our data suggest dysfunctional pre-attentive change-detection ability in patients with PD, particularly in the IFG.

Perceptions, clinical characteristics, and other factors associated with prolonged and high daily dose of benzodiazepine use among patients with anxiety or depressive disorders.

BACKGROUND: Benzodiazepines (BZDs) have been widely used to treat anxiety; however, the risk of adverse health effects caused by their long-term use is high. This study examined the factors associated with the duration and higher daily dose of BZDs use among a population with anxiety or depressive disorders. METHODS: A cross-sectional study design was used. Patients from a psychiatric outpatient department who had been prescribed BZDs were recruited. Data were collected from 250 patients. RESULTS: Nearly 94% of patients were long-term BZDs users. The mean duration of BZDs use was 5.5 years; and mean defined daily dose (DDD) of BZDs use, converted to diazepam milligram equivalent (DDD), was 1.53 DME-DDD. Patients who knew more about alternative treatments were less prone to use BZD longer. Patients aged 65 years or older and those with difficulty falling asleep were more prone to use BZDs longer. Patients who were currently taking BZDs at higher daily dose were those who felt more depressed, prescribed second generation antipsychotics, suffered from disrupted sleep, less aware of alternative treatments, had comorbid chronic physical illness, and were current smokers. LIMITATIONS: The cross-sectional study design limited its ability to confirm causal relationships. CONCLUSIONS: Long-term and excessive daily dose of BZDs use in patients with depressive or anxiety disorders needs to be noted. Providing information or program of non-pharmacological treatment in reducing anxiety and improving specific sleep disturbance is suggested. Elderly, suffering from depressive mood, had comorbid chronic physical illness need to be targeted for further intervention.

Altered functional connectivity between primary and secondary somatosensory areas in panic disorder.

Disturbance in the interpretation of bodily sensation has been widely reported in patients with panic disorder (PD). However, it remains substantially unknown whether patients with PD exhibit any defect in cortical somatosensory processing of non-threatening stimuli. Thus, the present study aimed to examine the functional integrity of the cortical somatosensory system in patients with PD using neurophysiological recordings. A total of 20 patients with PD and 20 healthy controls (HC) were recruited to investigate the cortical responses to median nerve stimulation through whole-head magnetoencephalographic (MEG) imaging. To comprehensively investigate all somatosensory functioning, we studied the regional activation of the primary somatosensory cortex (SI), contralateral (SIIc), and ipsilateral (SIIi) secondary somatosensory cortices, as well as functional connectivity among the SI, SIIc, and SIIi in alpha, beta, and gamma frequency bands. We found that patients with PD demonstrated a reduction in SI activity compared with those in the HC group. Furthermore, a significantly weaker gamma-band functional connectivity between SI and SIIc was found in the PD group relative to the HC group. Our data suggest that patients with PD exhibit abnormal responses to non-threatening (i.e., pain-free) stimuli in the cortical somatosensory system.

Novel patterned sapphire substrates for enhancing the efficiency of GaN-based light-emitting diodes.

In this study, a novel patterned sapphire substrate (PSS) was used to obtain mesa-type light-emitting diodes (LED), which can efficiently reduce the threading dislocation densities. Silicon nitride (Si3N4) was used as a barrier to form the PSS, replacing the commonly used silicon dioxide (SiO2). The refractive index of Si3N4 is 2.02, which falls between those of sapphire (1.78) and GaN (2.4), so it can be used as a gradient refractive index (GRI) material, enhancing the light extraction efficiency (LEE) of light-emitting diodes. The simulation and experimental results obtained indicate that the LEE is enhanced compared with the conventional PSS-LED. After re-growing, we observed that an air void exists on the top of the textured Si3N4 layer due to GaN epitaxial lateral overgrowth (ELOG). Temperature-dependent PL was used to estimate the internal quantum efficiency (IQE) of the PSS-LED and that of the PSS-LED with the Si3N4 embedded air void (PSA-LED). The IQE of the PSA-LED is 4.56 times higher than that of the PSS-LED. Then, a TracePro optical simulation was used to prove that the air voids will affect the final luminous efficiency. The luminous efficiency of the four different structures considered is ranked as Si3N4 (PSN-LED) > PSA-LED > PSS-LED with SiO2 (PSO-LED) > PSS-LED. Finally, we fabricated LED devices with different thickness of the Si3N4 barrier. The device shows the best luminance-current-voltage (LIV) performance when the Si3N4 thickness is 220 nm.

Sulfur isotope analysis for representative regional background atmospheric aerosols collected at Mt. Lulin, Taiwan.

Air pollution resulted from fossil fuel burning has been an environmental issue in developing countries in Asia. Sulfur-bearing compounds, in particular, are species that are regulated and monitored routinely. To assess how the species affect at local and global scales, regional background level has to be defined. Here, we report analysis of sulfur isotopes in atmospheric sulfate, the oxidation end product of sulfur species, in particulate phase collected at the Lulin observatory located at 2862 m above mean sea level in 2010. The averaged sulfate concentration for 44 selected samples is 2.7 ± 2.3 (1-σ standard deviation) µg m-3, and the averaged δ34S is 2.2 ± 1.6‰, with respect to the international standard Vienna Canyon Diablo Troilite. Regardless of the origins of air masses, no noticeable difference between the low-altitude Pacific and high-altitude free troposphere sulfate aerosols is observed. Also, no identifiable seasonal cycle in seen. Correlation analysis with respect to coal burning tracers such as lead and oil industry tracers such as vanadium shows sulfate concentration is in better correlation with vanadium (R2 = 0.86, p-value < 0.001) than with lead (R2 = 0.45, p-value < 0.001) but no statistically significant correlation is found in δ34S with any of physical quantities measured. We suggest the sulfate collected at Lulin can best represent the regional background level in the Western Pacific, a quantity that is needed in order to quantitatively assess the budget of sulfur in local to country scales.

Unraveling the Anomalous Surface-Charge-Dependent Osmotic Power Using a Single Funnel-Shaped Nanochannel.

Nanofluidic osmotic power, which converts a difference in salinity between brine and fresh water into electricity with nanoscale channels, has received more and more attention in recent years. It is long believed that to gain high-performance osmotic power, highly charged channel materials should be exploited so as to enhance the ion selectivity. In this paper, we report counterintuitive surface-charge-density-dependent osmotic power in a single funnel-shaped nanochannel (FSN), violating the previous viewpoint. For the highly charged nanochannel, the performance of osmotic power decreases with a further increase in its surface charge density. With increasing pH (surface charge density), the FSN enables a local maximum power density as high as ∼3.5 kW/m2 in a 500 mM/1 mM KCl gradient. This observation is strongly supported by our rigorous model where the equilibrium chemical reaction between functional carboxylate ion groups on the channel wall and protons is taken into account. The modeling reveals that for a highly charged nanochannel, a significant increase in the surface charge density amplifies the ion concentration polarization effect, thus weakening the effective salinity ratio across the channel and undermining the osmotic power generated.

The effect of anxiety on brain activation patterns in response to inspiratory occlusions: an fMRI study.

Respiratory sensations such as breathlessness are prevalent in many diseases and are amplified by increased levels of anxiety. Cortical activation in response to inspiratory occlusions in high- and low-anxious individuals was found different in previous studies using the respiratory-related evoked potential method. However, specific brain areas showed different activation patterns remained unknown in these studies. Therefore, the purpose of this study was to compare cortical and subcortical neural substrates of respiratory sensation in response to inspiratory mechanical occlusion stimuli between high- and low-anxious individuals using functional magnetic resonance imaging (fMRI). In addition, associations between brain activation patterns and levels of anxiety, and breathlessness were examined. Thirty-four (17 high- and 17 low-anxious) healthy non-smoking adults with normal lung function completed questionnaires on anxiety (State Trait Anxiety Inventory - State), and participated in a transient inspiratory occlusion fMRI experiment. The participants breathed with a customized face-mask while respiration was repeatedly interrupted by a transient inspiratory occlusion of 150-msec, delivered every 2 to 4 breaths. Breathlessness was assessed by self-report. At least 32 occluded breaths were collected for data analysis. The results showed that compared to the low-anxious group, the high-anxious individuals demonstrated significantly greater neural activations in the hippocampus, insula, and middle cingulate gyrus in response to inspiratory occlusions. Moreover, a significant relationship was found between anxiety levels and activations of the right inferior parietal gyrus, and the right precuneus. Additionally, breathlessness levels were significantly associated with activations of the bilateral thalamus, bilateral insula and bilateral cingulate gyrus. The above evidences support stronger recruitment of emotion-related cortical and subcortical brain areas in higher anxious individuals, and thus these areas play an important role in respiratory mechanosensation mediated by anxiety.