BEIRUT (AP) -- Thousands of defiant Syrians chanting "We are not afraid!" were met by security forces firing bullets and tear gas Friday in a crackdown on nationwide protests that left 42 people dead - many of them villagers trying to break an army blockade of the southern city where the six-week uprising began.

President Bashar Assad again unleashed deadly force in a determined effort to crush the revolt, the gravest challenge to his family's 40-year ruling dynasty.

Although still in control, he will struggle to recover legitimacy at home and abroad if he manages to stay in power. The United States slapped three top officials in his regime - including his brother - with sanctions and nations agreed to launch a U.N.-led investigation of Syria's crackdown.

Human rights groups say about 500 people have been killed since the uprising began.

Many of the 42 people killed Friday were in Daraa, said human rights activist Mustafa Osso, whose Syria-based group compiles casualty lists from the crackdown. He told The Associated Press that the death toll could rise,

Thousands of people from the outskirts of Daraa tried to break the military siege on the town Friday, but security forces opened fire, witnesses and human rights groups said.

A witness in Daraa said residents stayed indoors because the city has been under siege by the military since Monday, when thousands of soldiers backed by tanks and snipers stormed in. People were too afraid even to venture out to mosques for prayers, the witness said.

"We are in our houses but our hearts are in the mosques," the witness said, speaking by satellite telephone and asking that his name not be used for fear of reprisals.

A devastating picture was emerging of Daraa - which has been without electricity, water and telephones since Monday - as residents fled to neighboring countries. The uprising began in Daraa in mid-March, sparked by the arrest of teenagers who scrawled anti-regime graffiti on a wall.

"Nobody can move in (Daraa). They have snipers on the high roofs," a resident told the AP using a satellite phone. "They are firing at everything."

At the Jordanian side of the Syrian border, several Daraa residents who had just crossed said there is blood on the streets of the city.

"Gunfire is heard across the city all the time," one man said, asking that his name not be used for fear of retribution. "People are getting killed in the streets by snipers if they leave their homes."

An AP reporter at the border heard gunfire and saw smoke rising from different areas just across the frontier. Residents said the shooting has been constant for three weeks.

Syria has banned nearly all foreign media and restricted access to trouble spots, making it almost impossible to verify the dramatic events shaking one of the most authoritarian, anti-Western regimes in the Arab world.

Large demonstrations were reported Friday in the capital of Damascus, the central city of Homs, the coastal cities of Banias and Latakia, the northern cities of Raqqa and Hama, and the northeastern town of Qamishli near the Turkish border.

Outside Homs, thousands chanted "We don't love you!" and "Bye-bye, Bashar! We will see you in The Hague!" as the sound of gunfire crackled in the distance.

In Damascus' central Midan neighborhood, witnesses said about 2,000 people marched and chanted, "God, Syria and freedom only!" in a heavy rain, but security forces opened fire with bullets and tear gas, scattering them.

"Oh great Syrian army! Lift the blockade on Daraa!" protesters chanted in the Damascus suburb of Barzeh, according to a video posted by activists on YouTube.

The government had warned people against holding any demonstrations Friday and placed large banners around the capital that read: "We urge the brother citizens to avoid going out of your homes on Friday for your own safety." Syrian TV said the Interior Ministry has not approved any "march, demonstration or sit-in" and that such rallies seek only to harm Syria's security and stability.

A witness in Latakia said about 1,000 people turned out for an anti-government rally when plainclothes security agents with automatic rifles opened fire. He said he saw at least five people wounded. Like many witnesses contacted by the AP, he asked that his name not be used for fear of reprisal.

Assad's government says the protests are a foreign conspiracy by extremists and armed thugs, not true reform-seekers. Syrian TV said military and police forces came under attack Friday by "armed terrorists" in Daraa and Homs, killing four soldiers and three police officers. Two soldiers were captured, the report said. The station also said one of its cameramen was injured in Latakia by an armed gang.

Last week, Syria's Cabinet abolished the state of emergency, in place for decades, and approved a new law allowing the right to stage peaceful protests with the permission of the Interior Ministry.

But the protesters, enraged by the mounting death toll, are no longer satisfied with the changes and are increasingly seeking the regime's downfall.

Assad has acknowledged the need for reforms, offering overtures of change in recent weeks while brutally cracking down on demonstrations.

His regime has stepped up its campaign by sending out the army along with snipers and tanks. But on Friday, protesters came out in their thousands, defying the warnings and using the crackdown as a rallying cry.

Also Friday, the Muslim Brotherhood urged Syrians to demonstrate against Assad in the first time the outlawed group has openly encouraged the protests in Syria. The Brotherhood was crushed by Assad's father, Hafez, after staging an uprising against his regime in 1982.

"You were born free, so don't let a tyrant enslave you," said the statement, issued by the Brotherhood's exiled leadership.

The unrest in Syria - one of the most repressive and tightly controlled countries in the Middle East - has repercussions far beyond its borders because of its alliances with militant groups like Lebanon's Hezbollah and with Shiite powerhouse Iran.

If the regime in Syria falls, the instability has the potential to upend the regional power balance in a part of the world that already is riven with strife.

In recent weeks, there have been small signs that cracks are developing in the regime. Witnesses and human rights groups said Syrian army units clashed with each other over following Assad's orders to crack down on protesters in Daraa.

While the troops' infighting in Daraa does not indicate any decisive splits in the military, it is significant because Assad's army has always been the regime's fiercest defender.

Also, about 200 mostly low-level members of Syria's ruling Baath Party have resigned over the deadly crackdown.

"Although the regime can hold itself now, it has planted the seeds for its destruction eventually," Hilal Khashan, a political science professor at the American University of Beirut, told the AP.

The Obama administration hit three top Syrian officials as well as Syria's intelligence agency and Iran's Revolutionary Guard with sanctions over the crackdown.

The sanctions affect Assad's brother, Maher, who commands the Syrian army's Fourth Armored Division, which is accused of carrying out some of the most brutal acts in Daraa; Assad cousin Atif Najib, the former head of the Political Security Directorate in Daraa Province; and intelligence chief Ali Mamluk, the White House said.

"The United States strongly condemns the Syrian government's continued use of violence and intimidation against the Syrian people," according to the U.S. statement. "We call upon the Syrian regime and its supporters to refrain from further acts of violence and other human rights abuses against Syrian citizens seeking to express their political aspirations."

The penalties probably will have limited direct impact because none of the targets is believed to have any significant assets in U.S. banks. But officials said the move was aimed at sending a clear message to the Syrian people that those responsible for the crackdown will face consequences and that no one in the Syrian leadership will be immune.

Although Assad himself is not among those mentioned, officials said he could be named later if the crackdown continues. In a related move, the Commerce Department said it was revoking licenses for the export to Syria of items relating to VIP aircraft used to transport senior Syrian officials.

Syria is already under U.S. sanctions because of its designation as a "state sponsor of terrorism" by the State Department. The new ones extend the penalties to individuals.

Iran and its Revolutionary Guard Corps are under similar U.S. punishment. Officials said the new designation for the Revolutionary Guard would add another layer of penalties and make clear that Washington believes it is providing material support to help with the crackdown.

Meanwhile, diplomats say the U.N.'s nuclear watchdog agency is setting the stage for potential U.N. Security Council action on Syria as it prepares a report assessing that a Syrian target bombed by Israeli warplanes in 2007 was likely a secretly built nuclear reactor meant to produce plutonium.

Such a conclusion would back intelligence produced by Israel and the United States. Syria says the nearly finished building had no nuclear uses. It has repeatedly turned down requests by the International Atomic Energy Agency to revisit the site after allowing an initial 2008 inspection that found evidence of possible nuclear activities.

Three diplomats and a senior U.N. official said such an assessment - drawn up by IAEA chief Yukiya Amano - would be the basis of a Western-sponsored resolution at a meeting of the 35-nation IAEA board that condemns Syria's refusal to cooperate with the agency and kicks the issue to the U.N. Security Council. All spoke on condition of anonymity because the information they discussed was confidential.

Also Friday, nations agreed to launch a U.N.-led investigation of Syria's crackdown, demanding that Damascus halt the violence, release political prisoners and lift media restrictions.

The Geneva-based Human Rights Council said it would ask the U.N. Office of the High Commissioner for Human Rights to send a mission to investigate "all alleged violations of international human rights law and to establish the facts and circumstances of such violations and of the crimes perpetrated."

U.N. officials said the killings may include crimes against humanity.

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Associated Press writers Jamal Halaby at the Jordanian-Syrian border, Diaa Hadid in Cairo, Elizabeth A. Kennedy in Beirut, John Heilprin in Geneva, George Jahn in Vienna and Matthew Lee in Washington contributed to this report.